Tumor-resolving and histolytic medicaments and their use

ABSTRACT

Dehydrooligopeptides, some of which are known, demonstrate histolytic and tumor-resolving activity and may be used in medicaments causing the lysis of animal tissues and/or tumors in warm-blooded animals.

This is a continuation-in-part application of Ser. No. 862,896 filedDec. 21, 1977, now abandoned.

The present invention relates to the use as histolytic medicaments, ofdehydrooligopeptides, some of which are known.

In the following text, dehydrooligopeptides are to be understood ascompounds which are linked in a peptide-like manner and consist of fromtwo to ten aminoacid units and which have at least one double bond(corresponding to at least one dehydroaminoacid group).

The use of dehydrooligopeptides as medicaments has not previously beendisclosed.

It is known that a histolytic action can be achieved with substances ofthe most diverse nature. However, the general toxicity of such compoundsis usually so high that practical treatment regimens which can be easilymanipulated therapeutically and which do not harm the patients evenfurther scarcely exist.

Existing commercial products for use for corresponding indications arecytostatic agents, and cyclophosphamide may be mentioned here as anexample.

All the agents used hitherto exhibit an extremely high general toxicity.This is frequently so pronounced that it becomes necessary to interrupttherapy and thus the tumour diseases often end fatally.

The action of cyclophosphamide may be mentioned here as an example ofthe generally toxic action. Thus, M. H. N. TATTERSALL and J. S. TOBIASreport in The Lancet 1976/II, No. 7994, page 1,071: "In the case of manyanti-cancer agents, twice the dose which kills 10% of the animals (LD₁₀)is fatal for 90% of the animals (LD₉₀). FREI and FREIREICH (Advances inChemotherapy 2 (1965), 269) were able to demonstrate the significance ofusing agents such as cyclophosphamide in dosages which approached thetoxicity rate (LD₁₀). The decisive characteristic of these experimentswas the exponential increase observed in cell destruction with a low(arithmetic) increase in dose. The LD₁₀ dosage of cyclphosphamidedestroyed 99.999% of the tumour cells, but one eighth of this dose(which was far less toxic) destroyed only 90% of the tumour cells andwas therefore less active clinically by 5 log.

This observation is the reason for the generally widely-held view thatchemotherapy of cancer is only effective when it is not generallytoxic."

The present invention thus relates to the use of dehydrooligopeptides,some of which are known, as medicaments with a histolytic action, whichsubstantially avoid the above mentioned disadvantages of generally toxicactions; they are distinguished by a powerful histolytic action, whichdepends on the dose used, coupled with good general tolerance.

It has been found that the compounds which are dehydrooligopeptides andtheir salts possess a very good histolytic action in transplatedtumours.

In particular, it has been found that compounds which aredehydrooligopeptides of the following general formula I and their salts##STR1## in which

R₁ is a hydrogen atom, optionally substituted alkanoyl, optionallysubstituted alkenoyl, alkoxycarbonyl, optionally substituted aroyl,optionally substituted aralkanoyl or aralkenoyl, aralkoxycarbonyl,carbamoyl, optionally substituted hetero-aroyl, optionally substitutedlower alkylsulphonyl or optionally substituted arylsulphonyl,

R₂, R₇ and R₁₂ are the same or different and each is a hydrogen atom ora lower alkyl group,

R₃, R₈ and R₁₃ are the same or different and each is a hydrogen atom,straight-chain or branched optionally substituted lower alkyl,optionally substituted aryl optionally substituted aralkyl or aralkenyl,optionally substituted cycloalkyl or cycloalkenyl, indolylmethyl or anoptionally substituted heterocyclic-methyl group having from four toseven ring members and one or two hetero-atoms, or

one or more of R₂, R₇ and R₁₂, together with, in each case, the adjacentsubstituent R₃, R₈ or R₁₄ respectively, form(s) a divalent alkylenechain having three or four carbon atoms,

R₄ and R₉ each represent a hydrogen atom or a lower alkyl group, and

R₅ and R₁₀ are the same or different and each is a hydrogen atom oroptionally substituted lower alkyl,

R₆ and R₁₁ are the same or different and each is optionally substitutedalkyl, optionally substituted aryl, an optionally substitutedheterocyclic radical having from five to seven ring members and one ortwo hetero-atoms, optionally substituted aralkyl or optionallysubstituted aralkenyl, or

R₆ and/or R₁₁, together with R₅ or R₁₀, respectively, represent anoptionally substituted alkylene or alkylene chain having from three toseven carbon atoms,

R₁₄ is a hydrogen atom or optionally substituted lower alkyl or,together with R₁₃ and the carbon atom between them, represents analicyclic radical having from four to seven carbon atoms,

R₁₅ is hydroxyl, optionally substituted lower alkoxy or alkenyloxy,optionally substituted lower alkylthio or alkenylthio, optionallysubstituted arylthio, optionally substituted hydrazino, amino,optionally substituted lower alkylamino or dialkylamino or alkenylaminoor dialkenylamino or alkinylamino, optionally substituted arylamino,optionally substituted mono- or di-aralkylamino, a nitrogen-containingoptionally substituted hetero-cyclic radical having from four to sevenring members, optionally containing one or two further hetero-atoms,amino substituted by one or more optionally substituted alicyclicradicals having from three to seven ring members, or aralkyloxyamino,and

m, n, p and q are the same or different and each represents a FIG. 0 or1, with the proviso that m, n, p and q may not all be 1 at the sametime, have powerful histolytic properties.

Substances which are closely related chemically to thedehydrooligopeptides and which have a comparable action have nothitherto been disclosed.

It is new and completely surprising that dehydrooligopeptides displaysuch a highly pronounced histolytic action.

The active compounds according to the invention are thus an enrichmentof pharmacy.

In the general formula (I), the radicals R₁ to R₁₅ have the followingpreferred meanings:

An alkanoyl radical R₁ is preferably straight-chain or branched alkanoylhaving from two to six carbon atoms. Examples which may be mentionedare: acetyl, propionyl, butyryl and pentanoyl.

An alkenoyl radical R₁ is preferably straight-chain or branched alkenoylhaving from three to six carbon atoms. Examples which may be mentionedare: crotonyl and acrylyl.

Possible substituents of R₁ for the alkanoyl or alkenoyl radical R₁ arepreferably: from one to three halogen atoms, preferably fluorine andchlorine atoms, methoxy, ethoxy and hetero-aryl. Examples which may bementioned are chloroacetyl, trichloroacetyl, trifluoroacetyl andthiophenyl.

The straight-chain or branched lower alkoxycarbonyl radical R₁ ispreferably methoxy, ethoxy, propoxy or butoxycarbonyl, especiallytert.-butoxycarbonyl.

The optionally substituted aroyl radical R₁ is preferably benzoyl ornaphthoyl.

The optionally substituted aralkanoyl or aralkenoyl radical R₁preferably has from eight to twelve carbon atoms, in particular fromeight to ten carbon atoms. Examples which may be mentioned arephenacetyl, phenpropionyl, phenisopropionyl, cinnamoyl,β-methylcinnamoyl and phenylbutanoyl.

Possible substituents in the aroyl, aralkanoyl or aralkenoyl radical R₁are: from one to three halogen atoms, alkyl or alkoxy having up to threecarbon atoms, especially methoxy, trifluoromethyl, nitro or hydroxyl,optionally acylated with a lower organic acid radical.

The aralkoxycarbonyl radical R₁ denotes, in particular, aralkoxycarbonylhaving from eight to ten carbon atoms, most preferably thebenzyloxycarbonyl group.

An optionally substituted hetero-aroyl radical R₁ is understood as aheterocyclic radical which has five to seven ring members and cancontain from one to three hetero atoms which are the same or differentand each of which is a nitrogen, sulphur or oxygen atom and on whichthere is a carbonyl group. Examples of this radical which may bementioned are pyridinecarbonyl, thiophenecarbonyl, furanecarbonyl,pyrrolecarbonyl, oxazolecarbonyl, thiazolecarbonyl and pyrazinecarbonyl,optionally substituted by one or more halogen atoms, preferably fluorineand/or chlorine atoms, alkoxy having from one to four carbon atoms oralkyl having from one to four carbon atoms.

The optionally substituted lower alkylsulphonyl radical R₁ orarylsulphonyl radical R₁ preferably denotes methanesulphonyl orethanesulphonyl, or benzenesulphonyl or toluenesulphonyl, respectively.

A lower alkyl group as a radical R₂, R₇ or R₁₂ preferably denotes methylor ethyl.

If R₂, R₇ and R₁₂, together with, in each case, the adjacent substituentR₃, R₈ or R₁₄, respectively, form an alkylene chain with three to fourcarbon atoms, this means that R₂ forms a pyrrolidine or piperidine ringwith the associated nitrogen atom, the adjacent --CH-- group of thechain and R₃. Similarly in the case of R₇ and R₈ and, respectively, R₁₂and R₁₃.

A lower alkyl group as the radicals R₄ and R₉ preferably denotes methylor ethyl.

An optionally substituted straight-chain or branched lower alkyl oralkenyl radical R₃, R₈ and R₁₃ denotes a hydrocarbon radical, preferablyhaving from one to six carbon atoms and optionally a double or triplebond, such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec.-butyl or tert.-butyl, pentyl and hexyl with theirpossible isomers, and furthermore vinyl, ethinyl, propenyl or crotyl.

Substituents of the alkyl radical R₃, R₈ or R₁₃ which may be mentionedare: from one to three halogen atoms, hydroxyl groups, alkoxy groupshaving preferably from one to four carbon atoms, alkylthio groups havingpreferably from one to four carbon atoms, sulphhydryl groups, carbamidogroups and carboxyl groups.

Examples which may be mentioned of such substituted alkyl groups arecarboxymethyl, carboxyethyl, carbamoylmethyl, methylmercaptoethyl,trifluoromethyl, fluoromethyl, chloromethyl and hydroxymethyl.

An optionally substituted aryl group R₃, R₈ and R₁₃ in the generalformula I is preferably phenyl optionally substituted by one or morehalogen atoms, trifluoromethyl groups, hydroxyl groups, lower alkoxygroups having from one to four carbon atoms, alkyl groups having fromone to four carbon atoms, nitro groups or lower acyloxy groups havingfrom one to four carbon atoms.

An optionally substituted aralkyl or aralkenyl group R₃, R₈ and R₁₃preferably denotes phenylalkyl or phenylalkenyl having up to four carbonatoms and optionally a double or triple bond in the side chain, inparticular a CH₂ group. The aralkyl or aralkenyl radical can besubstituted by one or more halogen atoms, nitro, hydroxyl or methoxy oralkyl having from one to four carbon atoms.

An optionally substituted cycloalkyl or cycloalkenyl radical R₃, R₈ orR₁₃ represents monocyclic, bicyclic and tricyclic cycloalkyl orcycloalkenyl having preferably from 3 to 10, in particular 3, 5 or 6,carbon atoms. Examples which may be mentioned are optionally substitutedcyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl and adamantyl.

The cycloalkyl or cycloalkenyl radical R₃, R₈ or R₁₃ can be substitutedby one or more halogen atoms, nitro or hydroxyl groups, or alkoxy oralkyl groups having from one to four carbon atoms in each case.

An optionally substituted heterocyclic-methyl group denotes, inparticular, furfuryl, thenyl, pyrrolylmethyl, thiazolylmethyl,oxazolylmethyl, pyridinemethyl, piperidinemethyl, pyrazinemethyl ormorpholinemethyl, optionally substituted by from one to three halogenatoms or alkyl or alkoxy groups having from one to three carbon atoms,or by one nitro group.

Optionally substituted lower alkyl radicals R₅, R₁₀ and R₁₄ denote alkylhaving preferably from one to six, in particular one to two, carbonatoms, optionally substituted by halogen atoms, especially chlorine orfluorine atoms.

An optionally substituted alkyl group R₆ or R₁₁ in the general formula Idenotes a straight-chain or branched alkyl group having preferably fromone to six carbon atoms, in particular from one to three carbon atoms,optionally substituted by from one to three halogen atoms, preferablychlorine or fluorine atoms, or by alkoxy groups having from one to fourcarbon atoms, in particular methoxy groups.

An optionally substituted aryl radical R₆ or R₁₁ denotes, in particular,phenyl or naphthyl, optionally substituted by halogen atoms, preferablyfluorine and chlorine atoms, alkyl or alkoxy groups having from one tofour carbon atoms, methoxy and methyl groups being preferred, nitrogroups, hydroxyl groups, lower acyloxy groups having from one to fourcarbon atoms or amino, lower alkylamino or lower dialkylamino groups,preferably dimethylamino groups.

An optionally substituted heterocyclic radical R₆ or R₁₁ denotes aheterocyclic radical having from five to seven ring members and one ortwo hetero-atoms each of which may be, in particular, nitrogen, sulphuror oxygen. Examples which may be mentioned are thienyl, furyl, pyrrolyl,pyridyl, imidazolyl, pyrazolyl, pyrimidyl, pyrazinyl and morpholinyl,optionally substituted by halogen atoms, alkyl or alkoxy groups havingfrom one to four carbon atoms or hydroxyl, nitro or trifluoromethylgroups.

Optionally substituted aralkyl or aralkenyl groups R₆ and R₁₁ denote, inparticular, those having from seven to ten carbon atoms; phenylalkyl orphenylalkenyl groups having from one to four carbon atoms in thealiphatic moiety are particularly preferred, for example cinnamenyl andphenethyl, said aralkyl and aralkenyl groups being optionallysubstituted by one or more halogen atoms, alkyl or alkoxy groups havingpreferably from one to four carbon atoms, nitro groups andtrifluoromethyl groups.

In the general formula I, the radicals R₆ and R₁₁, together with R₅ andR₁₀ respectively, and the carbon atom, at the double bond, linking them,can form a cycloalkylidene ring or cycloalkenylidene ring havingpreferably from three to seven carbon atoms, in particularcyclohexylidene and cyclohexenylidene.

An optionally substituted lower alkoxy or alkenyloxy radical R₁₅ in thegeneral formula I denotes a straightchain or branched alkoxy oralkenyloxy radical having from one to six carbon atoms, in particularfrom one to four carbon atoms, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy, said alkoxyand alkenyloxy radicals being optionally substituted by one or morehalogen atoms or alkoxy groups having one or two carbon atoms.

A lower optionally substituted alkylthio or alkenylthio group R₁₅ is analkylthio or alkenylthio group having from one to six carbon atoms, inparticular from one to four carbon atoms. Substituents which may bementioned are from one to three halogen atoms or alkoxy groups or acarboxyl group.

An optionally substituted arylthio group R₁₅ is preferably phenylthio,optionally substituted by one to three halogen atoms or lower alkyl oralkoxy groups having preferably one or two carbon atoms in each case.

An optionally substituted hydrazine radical R₁₅ means that the hydrazineradical can be substituted by lower alkyl, optionally substituted aryl,preferably by phenyl, optionally substituted in turn by from one tothree halogen atoms or lower alkyl or alkoxy groups, or by aheterocyclic radical, having one or two nitrogen, oxygen and/or sulphuratoms, which in addition can be fused with a phenyl ring.

An optionally substituted lower monoalkylamino or monoalkenylamino ordialkenylamino or dialkylamino group R₁₅ denotes, in each case, such agroup having a straight-chain and/or branched alkyl or alkenylmoiety(ies) having preferably from one to six carbon atoms, such as, forexample, methylamino, ethylamino, pentylamino and1,1-dimethyl-2-propinylamino. The optional substituent(s) may, forexample, be halogen atoms, hydroxyl groups, alkoxy groups having one ortwo carbon atoms, an amino or lower monoalkylamino or dialkylaminogroup, a sulphonic acid radical or a phosphate radical or a heterocyclicradical, in particular a morpholine or imidazole ring.

An optionally substituted arylamino group R₁₅ preferably denotesphenylamino, optionally substituted by one to three halogen atoms oralkyl or alkoxy groups with preferably one or two carbon atoms in eachcase.

An optionally substituted monoaralkylamino or diaralkylamino group R₁₅preferably denotes monophenylalkylamino or diphenylalkylamino, havingfrom one to four carbon atoms in the aliphatic moiety in each case. Theoptional substituent(s) may be from one to three halogen atoms, or alkylor alkoxy groups, having from one to four carbon atoms in each case.

A heterocyclic group, containing a nitrogen atom, R₁₅, denotes aheterocyclic group, containing a nitrogen atom, having from four toseven ring members, optionally containing one or two furtherhetero-atoms, and optionally substituted by lower alkyl, lowerhydroxyalkyl or phenyl.

An amino group substituted by alicyclic radicals having from three toseven ring members, R₁₅, denotes cyclopropylamino, cyclobutylamino,cyclopentylamino, cyclohexylamino and cycloheptylamino group, preferablythe cyclohexylamino, or the correspondingly di-substituted amino group.This can be substituted by lower alkyl, alkenyl, alkinyl or aryl groups.

Some of the starting compounds for the preparation of the compounds ofthe general formula I according to the invention, that is to say thecorresponding 2,4-disubstituted 5(4H)-oxazolones, are known from theliterature. If they are not known, they can be prepared by the methodsdescribed in the literature. The reaction of acetylglycine withbenzaldehyde may be described here as an example. The reaction takesplace according to the equation ##STR2##

The reaction is carried out by mixing the two components in an equimolarratio in the presence of a condensing agent, usually acetic anhydride,which conveniently at the same time serves as a solvent, and of a basiccomponent, such as sodium acetate. After standing for several hours, themixture is worked up by diluting with water and recrystallising theresulting 4-benzylidene-2-methyl-5(4H)-oxazolone, which hasprecipitated, from ethyl acetate/petroleum ether.

Further examples of starting compounds which may be mentioned are:2-methyl-4-(2-thenylidene)-5(4H)-oxazolone,2-methyl-4-(2-naphthylmethylene)-5(4H)-oxazolone,4-(4-acetoxy-3-nitrobenzylidene)-2-methyl-5(4H)-oxazolone,4-ethoxymethylene-2-phenyl-5(4H)-oxazolone,4-cyclohexylmethylene-2-phenyl-5(4H)-oxazolone,4-benzylidene-2-trifluoromethyl-5(4H)-oxazolone,4-(1-methylpropylidene)-2-phenyl-5(4H)-oxazolone,2-phenyl-4-(2-thenylidene)-5(4H)-oxazolone,2-(3-pyridyl)-4-(2-thenylidene)-5(4H)-oxazolone,4-(1-methyl-3-phenyl-2-propenylidene)-2-phenyl-5(4H)-oxazolone,2-(1-acetamido-2-phenylvinyl)-4-(4-dimethyl-aminobenzylidene)-5(4H)-oxazolone,4-thenylidene-2-(3-trifluoromethylphenyl)-5(4H)-oxazolone,4-(2-cyclohexenylidene)-2-phenyl-5(4H)-oxazolone,4-(3-phenyl-2-propylidene)-2-phenyl-5(4H)-oxazolone,4-(α-methylbenzylidene)-2-phenyl-5(4H)-oxazolone,4-cyclohexylidene-2-phenyl-5(4H)-oxazolone, 4-(3-chlorobenzylidene)-2-(1-acetamido-2-phenylethyl)-5(4H)-oxazolone,4-(3-chlorobenzylidene)-2-(L-1-tert.-butoxycarbonylamino-2-phenylethyl-5(4H)-oxazolone,2-(1-acetamido-2-phenylvinyl)-4-(4-hydroxybenzylidene)-5(4H)-oxazolone,2-(1-propenyl)-4-(2-thenylidene)-5(4H)-oxazolone,2-ethoxymethyl-4-(2-thenylidene)-5(4H)-oxazolone,2-phenyl-4-benzylidene-5(4H)-oxazolone,2-(2-phenylvinyl)-4-benzylidene-5(4H)-oxazolone,2-[1-acetamido-2-(2-thienyl)vinyl]-4-(2-thenylidene)-5(4H)-oxazolone,2-[1-acetamido-2-(2-thienyl)vinyl]-4-(5-methylthenylidene-2)-5(4H)-oxazolone,2-[1-acetamido-2-(2-thienyl)-vinyl]-4-(4-nitrobenzylidene)-5(4H)-oxazolone,2-[2-(3,4,5-trimethoxyphenyl)vinyl]-4-(2-thenylidene)-5(4H)-oxazolone,2-methyl-4-(5-nitrothenylidene-2)-5(4H)-oxazolone,2-(2-thienyl)-4-(2-thenylidene)-5(4H)-oxazolone,2-phenyl-4-(4-pyridylmethylene)5(4H)-oxazolone,2-(4-nitrophenyl)-4-(2-thenylidene)-5(4H)-oxazolone,2-(3-thienylmethyl-4-(2-thenylidene)-5(4H)-oxazolone and2-[1-acetamido-2-(2-thienyl)vinyl]-4-(α-methyl-2-thienylidene)-5(4H)-oxazolone.

A number of the active compounds according to the invention are new;however, they can be prepared by known processes (compare D. G. DOHERTYet al., J. biol. Chem. 147 (1943), 617). They are obtained, for example,either by alkaline hydrolysis of the corresponding 2,4-disubstituted5(4H)-oxazolones or by aminolysis of the oxazolones with the alkalimetal salts, esters or amides of amioacids.

The reaction may be illustrated using the syntheses ofN-acetyldehydrophenylalanyldehydro-(3-chlorophenyl)alanine andN-acetyldehydrophenylalanyldehydro-(3-chlorophenyl)alanyl-L-tyrosine asexamples: ##STR3##

The reaction is usually carried out by stirring, or leaving the reactantor reactants to stand, in a diluent, such as aqueous acetone,tetrahydrofurane, dimethylformamide or an alcohol, usually at roomtemperature or a slightly elevated temperature, the reaction timedepending on the reactivity of the reactants, for example, the reactiontime may be from half an hour to twenty hours.

The mixture is worked up by acidifying with, for example, HCl, andevaporating off the organic solvent, whereupon the end product usuallyprecipitates.

If the reaction times are extremely long, partial racemisation cannot beexcluded, as can be seen from the optical rotation values of theproducts obtained.

In some cases it has proved to be appropriate, for reasons of purity andyield, to use an aminoacid ester instead of the free aminoacid in theaminolysis and to hydrolyse this ester after the condensation.

Examples which may be mentioned of the active compounds according to theinvention are: N-benzoyldehydro-β-(2-thienyl)alanine methyl ester,N-acetyldehydro-β-(2-thienyl)alanine ethyl ester,N-acetyldehydrophenylalanine, N-phenylacetyldehydro-β-(thienyl)alanine,N-acetyl-DL-phenylalanyldehydro-(3-chlorophenyl)alanine,N-tert.-butoxycarbonyl-L-phenylalanyldehydro-(3-chlorophenyl)alanine,L-phenylalanyldehydro-(3-chlorophenyl)alanine,N-acetyldehydrophenylalanyl-L-proline,N-acetyldehydrophenylalanyl-D-proline,N-acetyldehydrophenylalanyl-D-tyrosine,N-acetyldehydrophenylalanyl-L-leucine,N-acetyldehydrophenylalanyl-L-methionine,N-acetyldehydrophenylalanyl-L-aspartic acid,N-acetyldehydrophenylalanyl-L-glutamine,N-acetyldehydrophenylalanyl-DL-3-fluoroalanine,N-acetyldehydrophenylalanyl-L-serine,N-acetyldehydrophenylalanyl-L-tyrosine,N-acetyldehydrophenylalanylglycine,N-acetyldehydrophenylalanyl-L-(p-nitrophenyl)alanine,N-acetyldehydrophenylalanyl-DL-(p-chlorophenyl)alanine,N-trifluoroacetyldehydrophenylalanyl-L-tyrosine,N-acetyldehydro-(p-methylphenyl)alanyl-L-tyrosine,N-benzoyl-2-cyclohexylideneglycyl-L-tyrosine,N-benzoyl-2-(2-cyclohexenylidene)glycyl-L-tyrosine,N-acetyldehydro-3-(2-furyl)alanyl-L-tyrosine,N-acetyldehydro-3-cinnamenylalanyl-L-tyrosine,N-acetyldehydro-3-(2-naphthyl)-alanyl-L-tyrosine,N-benzoyldehydro-3-cyclohexylalanyl-L-tyrosine,N-benzoyldehydro-3-benzyl-3-methylalanyl-L-leucine,N-trifluoroacetyldehydrophenylalanyl-L-tyrosine tert.-butyl ester,N-benzoyldehydro-3-(2-thienyl)alanyl-L-proline,N-acetyldehydrophenylalanine (1-carboxy-1-cyclopentyl) amide,N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-phenacetyldehydro-3-(2-thienyl)alanyl-L-tyrosine tert.-butyl ester,N-phenacetyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-phenacetyldehydro-3-(2-thienyl)alanyl-L-leucine methyl ester,N-phenacetyldehydro-3-(2-thienyl)alanyl-L-leucine,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-benzoyldehydro-3-(2-thienyl)alanyl-L-(p-nitrophenyl)alanine,N-nicotinoyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanyl-L-tyrosine,N-benzoyldehydro-3-(2-thienyl)alanyl-L-proline,N-nicotinoyldehydro-3-(2-thienyl)alanyl-L-(p-nitrophenyl)alanine,N-benzoyl-3-methyl-3-(2-thienyl)dehydroalanyl-L-tyrosine,N-acetyldehydro-3-(2-thienyl)alanyl-D-tyrosine,N-cinnamoyldehydrophenylalanylglycine,N-benzoyldehydro-3-(2-thienyl)alanyl-L-phenylalanine,N-benzoyldehydro-3-(2-thienyl)alanyl-L-leucine,N-acetyldehydro-3-(2-thienyl)-L-phenylalanine,N-acetyldehydro-3-(2-thienyl)alanyl-L-leucine,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine methyl ester,N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine methyl ester,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine amide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine N'-hexylamide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine N'-cyclohexylamide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine N',N'-dimethylamide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine morpholide,N-acetyldehydrophenylalanyldehydrotyrosine,N-acetyldehydrophenylalanyldehydro-(p-nitrophenyl)alanine,N-acetyldehydrophenylalanyldehydro-(p-fluorophenyl)alanine,N-acetyldehydrophenylalanyldehydro-(4-dimethylaminophenyl)alanine,N-acetyldehydrophenylalanyldehydro-(3-chlorophenyl)alanine,N-acetyldehydrophenylalanyldehydro-(3-chlorophenyl)alanyl-L-tyrosine,N-acetyldehydrophenylalanyl-3-phenylserine,N-benzoyldehydrophenylalanylglycine,N-benzoyldehydrophenylalanyl-3-phenylserine,N-acetyldehydroleucylglycine, N-carbobenzoxyglycyldehydrophenylalanine,N-acetyldehydrophenylalanyl-L-alanine,N-acetyldehydrophenylalanyl-L-phenylalanine,N-acetyl-DL-phenylalanyldehydrophenylalanine,N-acetyl-dehydrophenylalanyldehydrophenylalanine,N-benzoyldehydrophenyl-alanyldehydrophenylalanine,N-benzoyldehydrophenylalanyldehydro-tyrosine,N-acetyldehydroleucyldehydrophenylalanine,N-carbobenzoxyglycyldehydrophenylalanyl-L-glutamic acid,N-carbobenzoxyglycycldehydrophenylalanylphenylserine,N-acetyldehydrophenyl-alanyldehydrophenylalanyl-L-alanine, -glycine,-L-leucine, -L-phenylalanine, -L-tyrosine, -L-proline, -3-phenylserine,-L-glutamic acid and -L-cystine, N-acetyldehydrophenylalanyl-D-glutamicacid, N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosinebenzyl ester,N-benzoyldehydro-3-(2-thienyl)-L-tyrosine N-benzylamide,N-acetyldehydro-3(2-thienyl)alanine N'-methylamide,N-acetyldehydro-3-(2-thienyl)alanine morpholide,N-acetyldehydro-3-(2-thienyl)alanine,N-cinnamoyldehydrophenylalanyl-L-tyrosine,N-benzoyldehydroisoleucyl-L-tyrosine, N-cinnamoyldehydrophenyl-alanine,N'-methylamide, N-cinnamoyldehydrophenylalanine1,1-dimethyl-2-propinylamide, N-cinnamoyldehydrophenylalaninemorpholide, N-benzoyl-3-methyl-3-cinnamenyldehydroalanyl-L-tyrosine,N-benzoyl-3-methylphenyldehydroalanyl-L-leucine,N-acetyldehydro-3-(2-thienyl)alanine N'-methylamide, andN-acetyl-dehydro-3-(2-thienyl)alanine N'-1,1-dimethyl-2-propinylamide.

Additional examples of compounds according to the invention which may bementioned are: N-crotonoyldehydro-3-(2-thienyl)-alanine, -alanine methylester, -alanaine thioethyl ester and alanine thiomethyl ester,N-ethoxyacetyldehydro-3-(2-thienyl)alanine methyl ester,N-acetyldehydrophenylalanyl-3-(5-methylthienyl-2)dehydroalanine,N-benzoyldehydrophenylalanine methyl ester,N-benzoyldehydrophenylalanine thioethyl ester,N-acetyldehydrophenylalanine thioethyl ester,N-acetyldehydrophenylalanine thiomethyl ester,N-acetyldehydro-3-(2-thienyl)alanine thiomethyl ester,N-acetyldehydro-3-(2-thienyl)alanine 2-carboxythioethyl ester,N-acetyldehydro-3-(2-thienyl)alanine thioethyl ester,N-acetyldehydro-3-(2-thienyl)alanine 4-chlorothiophenyl ester,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine thioethylester, N-acetyldehydrophenylalanine-3-(3-chlorophenyl)dehydroalaninethiomethyl ester, N-cinnamoyldehydrophenylalanine thiomethyl ester,N-(3-trifluoromethylbenzoyl)-3-(2-thienyl)alanine methyl ester,N-crotonyldehydro-3-(2-thienyl)alanine,N-acetyldehydro-3-(2-thienyl)alanyldehydro-3-(2-thienyl)alanine,N-benzoyl-dehydro-3-(2-thienyl)alanine,N-(3-trifluoromethylbenzoyl)-dehydro-3-(2-thienyl)alanine,N-acetyldehydro-3-(2-thienyl)alanyldehydro-3-(4-nitrophenyl)alanine,N-benzoyldehydrophenyl-alanine,N-acetyldehydro-3-(2-thienyl)alanyl-N-methylglycine,N-(3,4,5-trimethoxycinnamoyl)dehydro-3-(2-thienyl)alanyl-L-tyrosine,N-crotonoyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-acetyldehydro-3-(5-nitro-2-thienyl)alanyl-L-tyrosine,N-(2-thenoyl)dehydro-3-(2-thienyl)alanyl-L-tyrosine,N-crotonoyl-dehydro-3-(2-thienyl)alanyl-L-leucine,N-acetyldehydro-3-(2-thienyl)alanyl-O-methyl-L-tyrosine,N-acetyldehydro-3-(2-thienyl)alanyl-L-tryptophan,N-acetyldehydro-3-(2-thienyl alanyl-L-glycine,N-acetyldehydro-3-(2-thienyl)alanyl-2-(4-hydroxy-phenyl)-D-glycine,N-benzoyldehydrophenylalanyl-L-leucyglycine 4-methoxyphenylamide,N-acetyldehydro-3-(2-thienyl)alanyl-2-(1,4-cyclohexanedien-1-yl)-D-glycine, N-acetyldehydro-3-(2-thienyl)alanyl-L-glutamic acid,N-acetyldehydro-3-(2-thienyl)alanyl-L-leucine,N-acetyldehydro-3-(2-thienyl)alanyl-L-phenyl-alanine,N-acetyldehydro-3-(2-thienyl)alanyl-L-β-alanine,N-benzoyldehydrophenylalanylglycine,N-acetyldehydro-3-(2-thienyl)-alanyl-DL-valine, N-(2-thenoyl)dehydro-3-(2-thienyl)alanyl-2-(1,4-cyclohexanedien-1-yl)-D-glycine,N-acetyldehydro-3-(2-thienyl)alanyl-L-threonine,N-acetyldehydro-3-(2-thienyl)alanyl-L-aspartic acid,N-benzoylde-hydrophenylalanine-L-tryptophan,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanyl-L-leucine,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanyl-L-phenylalanine,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanylglycine,N-acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinetert.-butyl ester,N-acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinebenzyl ester,N-acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinemethyl ester, N-acetyldehydro-3-(2-thienyl)alanyl-N-methyl-L-tyrosinemethyl ester, N-acetyldehydro-3-(2-thienyl)alanyl-N-methyl-L-tyrosine,N-acetyldehydro-3-(3-nitro-4-hydroxyphenyl)alanyl-L-tyrosine tert.-butylester, N-acetyldehydro-3-(3-nitro-4-hydroxyphenyl)alanyl-L-tyrosine,N-benzoyldehydro-3-(4-pyridyl)alanyl-L-tyrosine methyl ester,N-benzoyldehydro-3-(4-pyridyl)alanyl-L-tyrosine,N-(4-nitrophenyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-(4-nitrophenyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine methylester,N-acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinetert.-butyl ester,N-acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosine,N-benzoyldehydroisoleucyl-L-tyrosine methyl ester,N-(2-thienyl)-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine,N-(2-thienyl)-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine tert.-butylester, N-(2-thienyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine benzylester, N-(2-thienyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine methylester, N-benzoyldehydrophenylalanyl-L-leucylglycine amide,N-benzoyldehydrophenylalanyl-L-propyl-L-leucylglycine amide,N-acetyldehydro-3-(2-thienyl)alanyl-2-methylalanine methyl ester,N-acetyldehydro-3-(2-thienyl)alanyl-2-methylalanine, the salt ofN-acetyldehydro-3-(2-thienyl)alanine with methylamine, with1,1-dimethylpropargylamine and with lithium, the salt ofN-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine with morpholine, withpiperidine, with ethylenediamine, with triethanolamine, withDL-canavanine, with L-arginine and L-lysine,N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine2O-dimethylaminopropylamide,N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine amide,N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine methylamide,N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine hydrazide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine 6-aminohexaneamide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine 4-aminobutane-amide,N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine hydrazide,N-ethoxyacetyldehydro-3-(2-thienyl)alanine 4-methylpiperazide,N-ethoxyacetyldehydro-3-(2-thienyl)alanine anilide,N-ethoxyacetyldehydro-3-(2-thienyl)alanine cyclohexylamide,N-ethoxyacetyldehydro-3-(2-thienyl)alanine amide,N-crotonyldehydro-3-(2-thienyl)alanine 4-methylpiperazide,N-crotonoyldehydro-3-(2-thienyl)alanine 3-dimethylaminopropylamide,N-crotonoyldehydro-3-(2-thienyl)alanine 6-aminohexane-amide,N-crotonoyldehydro-3-(2-thienyl)alanine 4-hydroxyanilide,N-acetyldehydrophenylalanyl-3-(2-thienyl)dehydroalanine methylamide,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine anilide,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine4-methylpiperazide,N-(3-trifluoromethylbenzoyl)-dehydro-3-(2-thienyl)alanine2-dimethylaminopropylamide,N-(3-trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine amide,N-acetyldehydro-3-(2-thienyl)alanyl-3-methyl-3-(thienyl)dehydroalaninehexylamide, N-nicotinoyl-3-(2-thienyl)dehydroalanine propargylamide,N-(2-thienylacetyl)dehydro-3-(2-thienyl)-alanine3-dimethylaminopropylamide, N-benzoyldehydro-3-(2-thienyl)alanine3-dimethylaminopropylamide, N-benzoyldehydro-3-(2-thienyl)alanineanilide, N-benzoyldehydro-3-(2-thienyl)alanine methylamide,N-benzoyldehydro-3-(2-thienyl)alanine hexylamide,N-benzoyldehydro-3-(2-thienyl)alanine propargylamide,N-benzoylhydro-3-(2-thienyl)alanine hydrazide,N-benzoyldehydrophenylalanine anilide, methylamide,1,1-dimethylpropargylamide, hexylamide, cyclohexylamide, morpholide,4-methoxyphenylhydrazide, 2-phenylcyclopropylamide,3,4,5-trimethoxyanilide, 3-dimethylaminopropylamide and propargylamide,N-acetyldehydro-3-(2-thienyl)alanine 2-(4-imidazolyl)ethylamide,hexylamide, 2-phenylcyclopropylamide, benzylamide,3-dimethylaminopropylamide, piperidide, 4-methylpiperazide,4-pheylpiperazide, 4-(2-hydroxyethyl)piperazide, amide,2,2-dimethylhydrazide, anilide, 4-methylcyclohexylamide,3-morpholinopropylamide, 1-phenylethylamide, 3-carboxypropylamide,hydrazide, 2-sulphonic acid ethylamide, 1-ethinylcyclohexylamide,benzyloxyamide, 2-hydroxyethylamide, esterified with phosphoric acid,and morpholide, N-acetyldehydro-3-(2-thienyl)alanine propargylamide,N-acetyldehydro-3-(2-thienyl)alanine 3,4,5-trimethoxyanilide andN-acetyldehydro-3-(2-thienyl)alanine-2-(benzothiazol-2-yl)hydrazide.

The compounds can exist both in the form of a racemate and in the formof isolated optical isomers having a definite absolute configuration. Inaddition, cis/trans isomers can occur in the synthesis, for example, ofN-benzoyldehydrophenylalanyl-L-leucine methyl ester. In some cases, forexample, in the case of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine,only one of the isomers is preferentially formed, as could bedemonstrated by 13-NMR spectroscopy.

The active compounds according to the invention have a histolyticaction, which depends on the dose which is given, preferably by localadministration. By local administration there are to be understoodherein as being included the following types of administration:subcutaneous and intracutaneous, administration.

Necroses usually occur in the immediate region of the point ofadministration, but occasionally also at a distance therefrom(lymphogenic). If the necrotic region breaks open, it is free fromputrid material even for a relatively long period, although in the caseof experimental animals feed, faeces, sawdust and other material comeinto contact with the open wound.

The activity of the third component of the immunohaemolytic complementsystem is considerably decreased.

The necrotic tissue is sharply divided from the surrounding healthytissue; it appears macroscopically and miscroscopically as if it were"stamped out".

The general behaviour of the experimental animals is not influenced bythe size of the necrosis. There is no poisoning of the entire organism.

In the acute test for intraveneous injection in rats, the LD₅₀ of thecompounds according to the invention is in the order of size of 300mg/kg.

A daily injection of 80 mg/kg in rabbits over a period of 27 days wastolerated completely without reaction.

As has been mentioned above, the present invention also includes the useof the active compounds according to the invention, for the treatment ofthose tissues in the field of medicine which prevent and interfere withthe course of normal biological functions.

Such tissues are, for example:

In addition, the compounds according to the invention can be used forfibrotic tissues of every type, in particular for the treatment ofkeloids, Ulcera crura, burn ulcers, decubital ulcers as well as claviand onychomycoses and scar tissue and for the therapy and prophylaxis ofemboli and thromboses.

The compounds according to the invention can also be used for resolvingmoles, atheromas and lipomas and for removing deep abscesses which,under certain circumstances, are fistulous.

The compounds according to the invention can additionally be used forthe regeneration of cavernomas and tuberculomas.

The compounds according to the invention can also be used for thescar-free regeneration of tissue defects in the case of leprosy andother skin, mucous membrane and epithelium defects of various origins,above all those which are caused by infections by bacteria, fungi andpathogens of tropical diseases, such as, for example, those ofleichmaniasis, framboesia, pinta and the like.

The present invention provides a pharmaceutical composition containingas active ingredient a compound of the invention in admixture with asolid or liquefied gaseous diluent, or in admixture with a liquiddiluent other than a solvent of a molecular weight less than 200(preferably less than 350) except in the presence of a surface activeagent.

The invention further provides a pharmaceutical composition containingas active ingredient a compound of the invention in the form of asterile and/or isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprisinga compound of the invention.

"Medicament" as used in this specification means physically discretecoherent portions suitable for medical administration. "Medicament indosage unit form" as used in this specification means physicallydiscrete coherent units suitable for medical administration eachcontaining daily dose or a multiple (up to four times) or sub-multiple(down to a fortieth) of a daily dose of the compound of the invention inassociation with a carrier and/or enclosed within an envelope. Whetherthe medicament contains a daily dose or, for example, a half, a third,or a quarter of a daily dose will depend on whether the medicament is tobe administered once or, for example, twice, three times or four times aday respectively.

The pharmaceutical compositions according to the invention may, forexample, take the form of ointments, gels, pastes, creams, sprays(including aerosols), lotions, suspensions, solutions and emulsions ofthe active ingredient in aqueous or non-aqueous diluents, syrups,granulates or powders.

The pharmaceutical compositions which are ointments, pastes, creams andgels can, for example, contain the usual diluents, e.g. animal andvegetable fats, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide or mixtures of these substances.

The pharmaceutical compositions which are powders and sprays can, forexample, contain the usual diluents, e.g. lactose, talc, silicic acid,aluminum hydroxide, calcium silicate, and polyamide powder or mixturesof these substances. Aerosol sprays can, for example, contain the usualpropellants, e.g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and emulsions can,for example, contain the customary diluents (with, of course, the abovementioned exclusion of solvents having a molecular weight below 200except in the presence of a surface-active agent), such as solvents,dissolving agents and emulsifiers; specific examples of such diluentsare water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils [for example ground nut oil], glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitol or mixtures thereof.

For parenteral administration, solutions and emulsions should besterile, and, if appropriate, blood-isotonic. Preferred injectionsolutions are those having a pH of from 7.0 to 9.5, most preferably from8 to 9. The compounds of the invention which are free acids may beconveniently dissolved in dilute physiologically acceptable bases andthen brought to the required pH by the addition of a dilutephysiologically acceptable acid.

Examples of physiologically acceptable bases which may be mentioned areinorganic hydroxides, carbonates and bicarbonates, in particular thoseof sodium and potassium. Examples of physiologically acceptable acidswhich may be mentioned are organic acids, such as citric acid, oxalicacid, lactic acid, benzoic acid, salicyclic acid and acetic acid, oralso inorganic acids, such as, for example, dilute hydrochloric orsulphuric acid.

The pharmaceutical compositions which are suspensions can contain theusual diluents, such as liquid diluents, e.g. water, ethyl alcohol,propylene glycol, surface-active agents (e.g. ethoxylated isostearylalcohols, polyoxyethylene sorbite and sorbitane esters),microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can alsocontain colouring agents and preservatives.

The pharmaceutical compositions according to the invention generallycontain from 1 to 90, usually from 5 to 50% of the active ingredient byweight of the total composition.

In addition to a compound of the invention, the pharmaceuticalcompositions and medicaments according to the invention can also containother pharmaceutically active compounds. They may also contain aplurality of compounds of the invention.

Any diluent in the medicaments of the present invention may be any ofthose mentioned above in relation to the pharmaceutical compositions ofthe present invention. Such medicaments may include solvents ofmolecular weight less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according tothe invention will generally be adapted, by virtue of their shape orpackaging, for medical administration and may be, for example, any ofthe following: ampoules. Some of these forms may be made up for delayedrelease of the active ingredient. Some, such as ampoules, include aprotective envelope which renders the portions of the medicamentphysically discrete and coherent.

The preferred daily dose for administration of the medicaments of theinvention is from 50 mg to 5 g of active ingredient most preferably from100 mg to 2 g of active ingredient.

The production of the above mentioned pharmaceutical compositions andmedicaments is carried out by any method known in the art, for example,by mixing the active ingredient(s) with the diluent(s) to form apharmaceutical composition (e.g. a solution or suspension) and thenforming the composition into the medicament (e.g. ampoules of injectionsolution or suspension).

This invention further provides a method of combating the abovementioned diseases in warm-blooded animals, which comprisesadministering to the animals a compound of the invention alone or inadmixture with a diluent or in the form of a medicament according to theinvention.

It is envisaged that these active compounds will be administeredparenterally (for example intramuscularly, intracutaneously orsubcutaneously, topically, preferably intracutaneously orsubcutaneously. Preferred pharmaceutical compositions and medicamentsare therefore those adapted for local administration, such as injectionsolutions and suspensions, ointments, gels, lotions and creams.Administration in the method of the invention is preferablysubcutaneous, intracutaneous intratumoral and peritumoral.

In general, it has proved advantageous to administer amounts of from 1mg to 100 mg preferably from 2 to 40 mg, per kg of body weight per dayto achieve effective results. Nevertheless, it can at times be necessaryto deviate from those dosage rates, and in particular to do so as afunction of the nature and body weight of the human or animal subject tobe treated, the individual reaction of this subject to the treatment,the type of formulation in which the active ingredient is administeredand the mode in which the administration is carried out, and the pointin the progress of the disease or interval at which it is to beadministered. Thus it may in some case suffice to use less than theabove mentioned minimum dosage rate, whilst other cases the upper limitmentioned must be exceeded to achieve the desired results. Where largeramounts are administered it can be advisable to divide these intoseveral individual administrations over the course of the day.

In the examples given below, the optical rotation was measured at c=2 indimethylformamide.

The metling points were determined in a Tottoli apparatus and areuncorrected.

EXAMPLE 1 N-Benzoyldehydro-β-(2-thienyl)alanine methyl ester

2 g of 2-phenyl-4-(2-thenylidene)-5(4H)-oxazolone are dissolved in 50 mlof absolute methanol and the solution is kept at room temperature for 16hours. The reaction solution is then evaporated, the residue is taken upin glacial acetic acid/ethylene chloride, the mixture is filtered andthe product is crystallised by concentrating the filtrate. 2 g (88.8% oftheory) of N-benzoyldehydro-β-(2-thienyl)alanine methyl ester of meltingpoint 162° C. are obtained.

C₁₅ H₁₃ NO₃ S: calculated: C 62.70%; H 4.56%; N 4.87%; S 11.16%; found:C 62.81%; H 4.67%; N 4.85%; S 11.18%.

EXAMPLE 2 N-Acetyldehydro-β-(2-thienyl)alanine ethyl ester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)-oxazolone and absoluteethanol analogously to Example 1; melting point 109°-110° C.

Yield 82%.

C₁₁ H₁₃ NO₃ S.H₂ O; calculated: C 51.42%; H 5.8%; N 5.4%; S 12.5%;found: C 41.80%; H 6.0%; N 5.4%; S 12.7%.

EXAMPLE 3 N-Acetyldehydrophenylalanine

is obtained by saponifying 2-methyl-4-benzylidene-5(4H)-oxazolone(preparation in the literature: Beilstein X, page 683); melting point188°-190° C.

EXAMPLE 4 N-Crotonoyldehydro-3-(2-thienyl)alanine methyl ester

is obtained from 2-(1-propenyl)-4-(2-thenylidene)-5(4H)-oxazolone andmethanol analogously to Example 1.

Melting point: 174°-176° C.; yield: 54% of theory.

C₁₂ H₁₃ NO₃ S; calculated: C 57.35%; H 5.21%; N 5.57%; S 12.76%. found:C 57.45%; H 5.31%; N 5.68%; S 12.55%.

EXAMPLE 5 N-Crotonoyldehydro-3-(2-thienyl)alanine thioethyl ester

is obtained from 2-(1-propenyl)-4-(2-thenylidene)-5(4H)-oxazolone andethylmercaptan analogously to Example 1.

Melting point: 176° C.; yield: 80% of theory.

C₁₃ H₁₅ NO₂ S₂ ; calculated: C 55.49%; H 5.33%; N 4.98%; S 22.79%;found: C 55.61%; H 5.44%; N 4.93%; S 22.96%.

EXAMPLE 6 N-Crotonoyldehydro-3-(2-thienyl)alanine thiomethyl ester

is obtained from 2-(1-propenyl)-4-(2-thenylidene)-5(4H)-oxazolone andmethylmercaptan analogously to Example 1.

Melting point: 178°-180° C.; yield: 63% of theory.

C₁₂ H₁₃ NO₂ S₂ ; calculated: C 53.91%; H 4.90%; N 5.24%; S 23.99%;found: C52.52%; H 4.91%; N 5.25%; S 24.21%.

EXAMPLE 7 N-Ethoxyacetyldehydro-3-(2-thienyl)alanine methyl ester

is obtained from 2-ethoxymethyl-4-(2-thenylidene)-5(4H)-oxazolone andmethanol analogously to Example 1.

Melting point: 102° C.; yield: 38% of theory.

C₁₂ H₁₅ NO₄ S; calculated: C 53.52%; H 5.61%; N 5.20%; S 11.91%; found:C 53.68%; H 5.52%; N 5.21%; S 11.78%.

EXAMPLE 8 N-Benzoyldehydrophenylalanine methyl ester

is obtained from 2-phenyl-4-benzylidene-5(4H)-oxazolone and methanolanalogously to Example 1.

Melting point: 141°-142° C.; yield: 65% of theory.

C₁₇ H₁₅ NO₃ ; calculated: C 72.6%; H 5.3%; N 5.0%; found: C 72.7%; H5.3%; N 4.9%.

EXAMPLE 9 N-Acetyldehydrophenylalanine thioethyl ester

is obtained from 2-methyl-4-benzylidene-5(4H)oxazolone andethylmercaptan analogously to Example 1 (in an autoclave for one week at50° C.).

Melting point: 106°-107° C.; yield: 7% of theory.

C₁₃ H₁₅ NO₂ S; calculated: C 62.62%; H 6.06%; N 5.62%; S 12.86%; found:C 62.89%; H 6.03%; N 5.65%; S 12.96%.

EXAMPLE 10 N-Acetyldehydrophenylalanine thiomethyl ester

is obtained from 2-methyl-4-benzylidene-5(4H)oxazolone andmethylmercaptan, in an autoclave for one week at 50° C., analogously toExample 1.

Melting point: 157°-158° C.; yield: 51% of theory.

C₁₂ H₁₃ NO₂ S; calculated: C 61.25%; H 5.57%; N 5.95%; S 13.63%; found:C 61.31%: H 5.62%: N 5.91%: S 13.51%.

EXAMPLE 11 N-Acetyldehydro-3-(2-thienyl)alanine thiomethyl ester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andmethylmercaptan, in an autoclave at 70° C., analogously to Example 1.

Melting point: 144°-145° C.; yield: 45% of the theory.

C₁₀ H₁₁ NO₂ S₂ ; calculated: C 49.77%; H 4.59%; N 5.80%; S 26.57%;found: C 49.61%; H 4.68%; N 5.75%; S 26.41%.

EXAMPLE 12 N-Acetyldehydro-3-(2-thienyl)alanine 3-carboxythioethyl ester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone and3-mercaptopropionic acid, in an autoclave, analogously to Example 1.

Melting point: 172°-174° C.; yield: 66.9% of theory.

C₁₂ H₁₃ NO₄ S₂ ; calculated: C 48.14%; H 4.38%; N 4.68%; S 21.42%;found: C 48.28%; H 4.40%; N 4.71%; S 21.44%.

EXAMPLE 13 N-Acetyldehydro-3-(2-thienyl)alanine thioethyl ester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andethylmercaptan analogously to Example 1.

Melting point: 110°-112° C.; yield: 98% of theory

C₁₁ H₁₃ NO₂ S₂ ; calculated: C 51.74%; H 5.13%; N 5.49%; S 25.11%;found: C 51.84%; H 5.12%; N 5.57%; S 24.97%.

EXAMPLE 14 N-Acetyldehydro-3-(2-thienyl)alanine 4-chlorothiophenyl ester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone and4-chlorophenylmercaptan, in the presence of triethylamine, analogouslyto Example 1.

Melting point: 177°-179° C.; yield: 48.8% of theory.

C₁₅ H₁₂ ClNO₂ S₂ ; calculated: C 53.33%; H 3.58%; Cl 10.49%; N 4.15%; S18.98%; found: C 53.45%; H 3.57%; Cl 10.63%; N 4.13%; S 19.10%.

EXAMPLE 15 N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alaninethioethyl ester

is obtained from2-(3-trifluoromethylphenyl)-4-(2-thenylidene)-5(4H)oxazolone andethylmercaptan, in the presence of NaH, analogously to Example 1.

Melting point: 139°-140° C.; yield: 50% of theory.

C₁₇ H₁₄ F₃ NO₂ S₂ ; calculated: C 52.98%; H 3.66%; F 14.79%; N 3.63%; S16.64%; found: C 53.18%; H 3.60%; F 14.9%; N 3.50%; S 16.63%.

EXAMPLE 16 N-Benzoyldehydrophenylalanine thioethyl ester

is obtained from 2-phenyl-4-benzylidene-5(4H)oxazolone andethylmercaptan analogously to Example 1.

Melting point: 150° C. (decomposition); yield: 47% of theory.

C₁₈ N₁₇ NO₂ S; calculated: C 69.43%; H 5.50%; N 4.50%; S 10.30%; found:C 69.27%; H 5.55%; N 4.54%; S 10.32%.

EXAMPLE 17 N-Acetyldehydrophenylalanine-3-(3-chlorophenyl)dehydroalaninethiomethyl ester

is obtained from4-(3-chlorobenzylidene)-2-(1-acetamido-2-phenylvinyl)-5(4H)oxazolone andmethylmercaptan, in a pressure flask for one week, analogously toExample 1.

Melting point: 166°-167° C.; yield: 38.8% of theory.

C₂₁ H₁₉ ClN₂ O₃ S; calculated: C 60.79%; H 4.61%; Cl 8.54%; N 6.75%; S7.73%; found: C 60.74%; H 4.48%; Cl 8.58%; N 6.82%; S 7.80%.

EXAMPLE 18 N-Cinnamoyldehydrophenylalanine thiomethyl ester

is obtained from 2-(2-phenylvinyl)-4-benzylidene-5(4H)oxazolone andmethylmercaptan, in an autoclave for one week, analogously to Example 1.

Melting point: 182°-183° C.; yield 28.5% of theory.

C₁₉ H₁₇ NO₂ S; calculated: C 70.56%; H 5.30%; N 4.33%; S 9.91%; found: C70.40%; H 5.39%; N 4.41%; S 9.61%.

EXAMPLE 19 N-(3-Trifluoromethylbenzoyl)-3-(2-thienyl)alanine methylester

is obtained from2-(3-trifluoromethylphenyl)-4-(2-thenylidene)-5(4H)oxazolone andmethanol, in the presence of sodium hydride, analogously to Example 1.

Melting point: 117°-118° C.; yield: 64.8% of theory.

C₁₆ H₁₂ F₃ NO₃ S; calculated: C 54.08%; H 3.04%; F 16.04%; S 9.03%;found: C 54.01%; H 3.47%; F 15.90%; S 9.05%.

EXAMPLE 20 N-Phenylacetyldehydro-β-(thienyl)alanine

is obtained by saponifying 2-benzyl-4(2-thenylidene)-5(4H)-oxazolone;melting point 193°-195° C.; yield: 8.2% of theory.

C₁₅ H₁₃ NO₃ S; calculated: C 62.70%; H 4.56%; N 4.88%; S 11.16%; found:C 62.68%; H 4.55%; N 4.96%; S 11.26%.

EXAMPLE 21 DL-N-Acetylphenylalanyldehydro-(3-chlorophenyl)alanine

1.8 g (0.005 mol) of2-(1-acetamido-2-phenylethyl)-4-(3-chlorobenzylidene)-5(4H)-oxazoloneare suspended in 7 ml of acetone, and 7.5 ml of 2 N NaOH are added.

After stirring for half an hour, the reaction solution is acidified topH 3 with citric acid and the precipitate which separates out iffiltered off and washed until neutral.

Melting point: 195°-196° C.; yield: 1.6 g (84.2% of theory).

C₂₀ H₁₉ ClN₂ O₄ ; calculated: C 62.10%; H 4.95%; Cl 9.17%; N 7.24%;found: C 62.31%; H 4.77%; Cl 9.03%; N 7.31%.

EXAMPLE 22L-N-tert.-Butoxycarbonylphenylalanyldehydro-(3-chlorophenyl)alanine

is obtained from2-(1-tert.-butoxycarbonylamido-2-phenylethyl)-4-(3-chlorophenyl)-5-(4H)-oxazoloneanalogously to Example 21, with recrystallisation from aqueous acetone.Melting point: 173° C. (decomposition), [α]_(D) ²⁰ +78.6° (c=1;dimethylformamide), yield: 83.3% of theory.

C₂₃ H₂₅ ClN₂ O₅ ; calculated: C 62.09%; H 5.66%; Cl 7.97%; N 6.30%;found: C 62.26%; H 5.66%; Cl 7.95%; N 6.44%.

EXAMPLE 23 L-Phenylalanyldehydro-(3-chlorophenyl)alanine

is obtained from 2.5 g of the above compound by dissolving in 15 ml ofanhydrous trifluoroacetic acid, allowing the mixture to stand at roomtemperature for one hour, evaporating, taking up the residue in water,adjusting the pH of the solution to 8 with NH₃ and evaporating thesolution until crystallisation starts.

Melting point: 235°-236° C.; [α]_(D) ²⁰ -31.5° (c=1; dimethylformamide);yield: 1.7 g (89.5% of theory).

C₁₈ H₁₇ ClN₂ O₃ ; calculated: C 62.70%; H 4.97%; Cl 10.28%; N 8.13%;found: C 62.55%; H 5.35%; Cl 10.15%; N 8.19%.

EXAMPLE 24 N-Acetyldehydro-3-(2-thienyl)alanine

is obtained from 4-thenylidene-2-methyl-5(4H)oxazolone analogously toExample 21.

Melting point: 222°-223° C.; yield: 5.7% of theory.

C₉ H₉ NO₃ S; calculated: C 51.17%; H 4.30%; N 6.63%; S 15.18%; found: C51.21%; H 4.37%; N 6.65%; S 15.32%.

EXAMPLE 25N-Acetyldehydrophenylalanyl-3-(5-methylthienyl-2)dehydroalanine

is obtained from4-(5-methylthenylidene)-2-(1-acetamido-2-phenylvinyl)-5(4H)-oxazoloneanalogously to Example 21.

Melting point: 193°-194° C.; yield: 40% of theory.

C₁₉ H₁₈ N₂ O₄ S; calculated: C 61.61%; H 4.90%; N 7.56%; S 8.66%; found:C 61.54%; H 4.96%; N 7.55%; S 8.70%.

EXAMPLE 26 N-Crotonoyldehydro-3-(3-thienyl)alanine

is obtained from 2-(1-propenyl)-4-(2-thenylidene)-5(4H)-oxazoloneanalogously to Example 21.

Melting point: 226° C.; yield: 88% of theory.

C₁₁ H₁₁ NO₃ S; calculated: C 55.68%; H 4.67%; N 5.90%; S 13.51%; found:C 55.23%; H 4.71%; N 6.03%; S 13.96%.

EXAMPLE 27N-Acetyldehydro-3-(2-thienyl)alanyldehydro-3-(2-thienyl)alanine

is obtained from2-[1-acetamido-2(2-thienyl)vinyl]-4-(2-thenylidene)-5(4H)oxazoloneanalogously to Example 21.

Melting point: 218° C.; yield: 80% of theory.

C₁₆ H₁₄ N₂ O₄ S₂ ; calculated: C 53.02%; H 3.89%; N 7.73%; S 17.69%;found: C 52.99%; H 3.94%; N 7.96%; S 17.70%.

EXAMPLE 28 N-Benzoyldehydro-3-(2-thienyl)alanine

is obtained from 2-phenyl-5-(2-thenylidene)-5(4H)oxazolone analogouslyto Example 21.

Melting point: 235° C.; yield: 94% of theory.

C₁₄ H₁₁ NO₃ S; calculated: C 61.52%; H 4.06%; N 5.12%; S 11.74%; found:C 61.50%; H 4.08%; N 5.14%; S 11.70%.

EXAMPLE 29 N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine

is obtained from4-thenylidene-2-(3-trifluoromethylphenyl)-5(4H)oxazolone analogously toExample 21.

Melting point: 200°-202° C.; yield: 93% of theory.

C₁₅ H₁₀ F₃ NO₃ S; calculated: C 52.76%; H 2.96%p F 16.70%; N 4.10%; S9.39%; found: C 52.89%; H 2.92%; F 16.60%; N 4.18%; S 9.36%.

EXAMPLE 30N-Acetyldehydro-3-(2-thienyl)alanyldehydro-3-(4-nitrophenyl)alanine

is obtained from4-(4-nitrobenzylidene)-2-[1-acetamido-2-(2-thienyl)vinyl]-5(4H)oxazoloneanalogously to Example 21.

Melting point: 196°-197° C.; yield: 55.7% of theory.

C₁₈ H₁₅ N₃ O₆ S; calculated: C 53.86%; H 3.77%; N 10.47%; S 7.99%;found: C 53.80%; H 3.81%; N 10.52%; S 7.85%.

EXAMPLE 31 N-Benzoyldehydrophenylalanine

is obtained from 4-benzylidene-2-phenyl-5(4H)oxazolone analogously toExample 21.

Melting point: 25° C.; yield: 88% of theory.

C₁₆ H₁₃ NO₃ ; calculated: C 71.90%; H 4.90%; N 5.24%; found: C 71.98%; H4.80%; N 5.25%.

The examples which follow were formed accoring to the following generalinstructions:

0.025 mol of the aminoacid to be subjected to condensation is suspendedin 10 ml of acetone, 25 ml of 1 N NaOH are added whilst stirring and thesolution formed is mixed with a suspension of the appropriatelysubstituted 5(4H)-oxazolone in acetone. The mixture is stirred at roomtemperature for 1/2 to 20 hours, depending on the reactivity of theaminoacid. 25 ml of 1 n HCl are then added to the filtered reactionsolution and the acetone is distilled off in vacuo. The desired endproduct crystallises out of the aqueous phase and is recrystallised fromaqueous alcohol.

EXAMPLE 32 N-Acetyldehydrophenylalanyl-L-proline

is obtained from 2-methyl-4-phenyl-5(4H)-oxazolone and L-proline.

Melting point: 152°-155° C.; [α]_(D) ²⁰ +69.5°; yield: 59% of theory.

C₁₆ H₁₈ N₂ O₄.1/2H₂ O; calculated: C 61.72%; H 6.15%; N 9.00%; found: C62.15%; H 6.43%; N 8.96%.

EXAMPLE 33 N-Acetyldehydrophenylalanyl-D-proline

Melting point: 151°-253° C.; [α]_(D) ²⁰ -69.6°; yield: 55% of theory.

C₁₆ H₁₈ N₂ O₄ ; calculated: C 61.72%; H 6.15%; N 9.0%; found: C 61.75%;H 6.30%; N 8.94%.

EXAMPLE 34 N-Acetyldehydrophenylalanyl-D-tryosine

Melting point: 210° C.; [α]_(D) ²⁰ -43.4° (c=2; pyridine); yield: 61.3%of theory.

C₂₀ H₂₀ N₂ O₅ ; calculated: C 65.21%; H 5.47%; N 7.60%; found: C 64.56%;H 5.86%; N 7.77%.

EXAMPLE 35 N-Acetyldehydrophenylalanyl-L-leucine

Melting point: 206°-207° C.; [α]_(D) ²⁰ -22.5°; yield: 65.7% of theory.

C₁₇ H₂₂ N₂ O₄ ; calculated: C 64.13%; H 6.97%; N 8.80%; found: C 64.26%;H 7.31%; N 8.78%.

EXAMPLE 36 N-Acetyldehydrophenylalanyl-L-methionine

Melting point: 91°-93° C., [α]_(D) ²⁰ -74.4°; yield: 70% of theory.

C₁₆ H₂₀ N₂ O₄ S; calculated: C 57.12%; H 5.99%; N 8.33%; S 9.53%; found:C 57.02%; H 6.03%; N 8.40%; S 9.46%.

EXAMPLE 37 N-Acetyldehydrophenylalanyl-L-aspartic acid

Melting point: 182°-184° C.; [α]_(D) ²⁰ -46.65°; yield: 63.5% of theory.

C₁₅ H₁₆ N₂ O₆.H₂ O; calculated: C 53.25%; H 5.36%; N 8.28%; found: C53.48%; H 4.92%; N 8.32%.

EXAMPLE 38 N-Acetyldehydrophenylalanyl-L-glutamine

Melting point: 188° C; [α]_(D) ²⁰ -74.5°; yield: 54% of theory.

C₁₆ H₁₉ N₃ O₅ ; calculated: C 57.65%; H 5.75%; N 12.61%; found: C58.17%; H 5.79% N 13.16%.

EXAMPLE 39 N-Acetyldehydrophenylalanyl-DL-3-fluoroalanine

Melting point: 180° C. (decomposition); yield: 58.7% of theory.

C₁₄ H₁₅ FN₂ O₄ ; calculated: C 57.14%; H 5.14%; F 6.46%; N 9.52%; found:C 57.22%; H 5.22%; F 6.30%; N 9.58%.

EXAMPLE 40 N-Acetyldehydrophenylalanyl-L-serine

Melting point: 179° C. (decomposition); [α]_(D) ²⁰ +1.15°; yield: 48.5%of theory.

C₁₄ H₁₆ N₂ O₅ ; calculated: C 57.35%; H 5.52%; N 9.58%; found: C 57.48%;H 5.47%; N 9.66%.

EXAMPLE 41 N-Acetyldehydrophenylalanyl-L-tyrosine

Melting pint: 219°-220° C.; preparation in the literature.

EXAMPLE 42 N-Acetyldehydrophenylalanylglycine

Melting point: 191°-192° C.; preparation in the literature.

EXAMPLE 43 N-Acetyldehydrophenylalanyl-L-(p-nitrophenyl)alanine

Melting point: 192°-193° C. (from ethanol/petroleum ether/isopropylether); [α]_(D) ²⁰ -110.7°; yield: 70.3% of theory.

C₂₀ H₁₉ N₃ O₆ ; calculated: C 60.45%; H 4.82%; N 10.58%; found: C60.40%; H 4.90%; N 10.43%.

EXAMPLE 44 N-Acetyldehydroalanyl-DL-(p-chlorophenyl)alanine

Melting point: 214°-215° C. (from ether/petroleum ether); yield: 66.9%of theory.

C₂₀ H₁₉ ClN₂ O₄ ; calculated: C 62.10%; H 4.95%; Cl 9.17%; N 7.24%;found: C 62.39%; H 5.02%; Cl 9.14%; N 7.11%.

EXAMPLE 45 N-Acetyldehydro(p-methylphenyl)alanyl-L-tyrosine

Melting point: 220°-221° C.; [α]_(D) ²⁰ -38.5°; yield: 47.6% of theory.

C₂₁ H₂₂ N₂ O₅ ; calculated: C 65.95%; H 5.80%; N 7.33%; found: C 65.96%;H 5.80%; N 7.16%.

EXAMPLE 46 N-Benzoyl-2-cyclohexylideneglycyl-L-tyrosine

Melting point: 121° C.; [α]_(D) ²⁰ -0.5°; yield: 75.8% of theory.

C₂₄ H₂₆ N₂ O₅ ; calculated: C 68.23%; H 6.20%; N 6.63%; found: C 68.16%;H 6.18%; N 6.65%.

EXAMPLE 47 N-Benzoyl-2-(2-cyclohexenylidene)glycyl-L-tyrosine

Melting point: 126° C.; [α]_(D) ²⁰ -5.7°; yield: 60% of theory.

C₂₄ H₂₄ N₂ O₅ ; calculated: C 68.56%; H 5.75%; N 6.66%; found: C 68.46%;H 5.70%; N 6.56%.

EXAMPLE 48 N-Acetyldehydro-3-(2-furyl)alanyl-L-tyrosine

Melting point: 217° C. (ethanol/petroleum ether); [α]_(D) ²⁰ -29.1°;yield: 31% of theory.

C₁₈ H₁₈ N₂ O₆ ; calculated: C 60.33%; H 5.06%; N 7.82%; found: C 60.37%;H 5.11%; N 7.70%.

EXAMPLE 49 N-Acetyldehydro-3-cinnamenylalanyl-L-tyrosine

Melting point: 220°-221° C.; [α]_(D) ²⁰ -44.2°; yield: 57.3% of theory.

C₂₂ H₂₂ N₂ O₅ ; calculated: C 66.99%; H 5.62%; N 7.10%; found: C 66.80%;H 5.64%; N 7.06%.

EXAMPLE 50 N-Acetyldehydro-3-(2-naphthyl)alanyl-L-tyrosine

Melting point: 221°-222° C. (precipitated from ethyl acetate/isopropanolwith petroleum ether); [α]_(D) ²⁰ -11.6° (c=2; from methanol); yield:55.7% of theory.

C₂₄ H₂₂ N₂ O₅ ; calculated: C 68.89%; H 5.30%; N 6.70%; found: C 69.04%;H 5.37%; N 6.65%.

EXAMPLE 51 N-Benzoyldehydro-3-cyclohexylalanyl-L-tyrosine

Melting point: 126°-128° C.; [α]_(D) ²⁰ +0.8° (c=1; dimethylformamide);yield: 60.3% of theory.

C₂₅ H₂₈ N₂ O₅ ; calculated: C 68.79%; H 6.46%; N 6.42%; found: C 68.59%;H 6.32%; N 6.24%.

EXAMPLE 52 N-Benzoyldehydro-3-benzyl-3-methylalanyl-L-leucine

Melting point: 98°-99° C.; [α]_(D) ²⁰ -14.1°; yield: 39% of theory.

C₂₄ H₂₈ N₂ O₄ ; calculated: C 70.57%; H 6.91%; N 6.86%; found: C 70.47%;H 6.74%; N 6.92%.

EXAMPLE 53 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-proline

Melting point: 125° C. (ill-defined); [α]_(D) ²⁰ +2.0°; yield: 52% oftheory.

C₁₉ H₁₈ N₂ O₄ S; calculated: C 61.60%; H 4.90%; N 7.56%; S 8.66%; found:C 61.59%; H 4.80%; N 7.50%; S 8.79%.

EXAMPLE 54 N-Acetyldehydrophenylalanin-(1-carboxy-1-cyclopentyl) amide

Melting point: 217° C. (decomposition); yield: 50.7% of theory.

C₁₇ H₂₀ N₂ O₄ ; calculated: C 64.54%; H 6.37%; N 8.86%; found: C 64.85%;H 6.55%; N 8.41%.

EXAMPLE 55 N-Acetyldehydro-3-(2-thienyl)analyl-L-tyrosine

Melting point: 227°-228° C.; [α]_(D) ²⁰ -36.75°; yield: 71.06% oftheory.

C₁₈ H₁₈ N₂ O₅ S; calculated: C 57.74%; H 4.85%; N 7.48%; S 8.56%; found:C 57.61%; H 4.84%; N 7.49%; S 8.62%.

EXAMPLE 56 N-Acetyldehydro-3-(2-thienyl)alanyl-N-methylglycine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andN-methylglycine.

Melting point: 207°-208° C.; yield: 82.4% of theory.

C₁₂ H₁₄ NO₄ S; calculated: C 51.05%; H 5.00%; N 9.92%; S 11.36%; found:C 51.19%; H 5.09%; N 9.97%; S 11.19%.

EXAMPLE 57N-(3,4,5-Trimethoxycinnamoyl)dehydro-3-(2-thienyl)alanyl-L-tyrosine

is obtained from2-[2-(3,4,5-trimethoxyphenyl)vinyl]-4-(2-thenylidene)-5(4H)oxazolone andL-tyrosine.

Melting point: 148°-150° C.; yield: 92.2% of theory.

C₂₈ H₂₈ N₂ O₈ S; calculated: C 60.86%; H 5.11%; N 5.07%; S 5.80%; found:C 60.74%; H 5.15%; N 5.07%; S 5.79%.

EXAMPLE 58 N-Crotonoyldehydro-3-(2-thienyl)alanyl-L-tyrosine

is obtained from 2-(1-propenyl)-4-(2-thenylidene)-5(4H)-oxazolone andL-tyrosine.

Melting point: 157° C.; yield: 51% of theory.

C₂₀ H₂₀ NO₅ S; calculated: C 59.99%; H 5.03%; N 7.00%; S 8.01%; found: C60.34%; H 4.97%; N 6.63%; S 7.51%.

EXAMPLE 59 N-Acetyldehydro-3-(5-nitrothienyl-2)alanyl-L-tyrosine

is obtained from 2-methyl-4-(5-nitrothenylidene-2)-5(4H)oxazolone andL-tyrosine.

Melting point: 148°-157° C.; yield: 54.6% of theory.

C₁₈ H₁₇ N₃ O₇ S; calculated: C 51.55%; H 4.09%; N 10.02%; S 7.65%;found: C 51.36%; H 4.11%; N 10.01%; S 7.64%.

EXAMPLE 60 N-(2-Thenoyl)dehydro-3-(2-thienyl)alanyl-L-tyrosine

is obtained from 2-(2-thienyl)-4-(2-thenylidene)-5(4H)oxazolone andL-tyrosine.

Melting point: 140°-150° C.; yield: 72% of theory.

C₂₁ H₁₈ N₂ O₅ S₂ ; calculated: C 57.00%; H 4.10%; N 6.33%; S 14.49%;found: C 57.01%; H 4.28%; N 6.35%; S 14.12%.

EXAMPLE 61 N-Crotonoyldehydro-3-(2-thienyl)alanyl-L-leucine

is obtained from 2-(1-propenyl)-4-(2-thenylidene)-5(4H)oxazolone andL-leucine.

Melting point: 176° C.; yield: 73% of theory.

C₁₇ H₂₂ N₂ O₄ S; calculated: C 58.27%; H 6.33%; N 7.99%; S 9.15%; found:C 58.18%; H 6.26%; N 7.97%; S 9.23%.

EXAMPLE 62 N-Acetyldehydro-3-(2-thienyl)alanyl-O-methyl-L-tyrosine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andO-methyl-L-tyrosine.

Melting point: 236° C.; yield: 90% of theory.

C₁₉ H₂₀ N₂ O₅ S; calculated: C 53.75%; H 5.19%; N 7.21%; S 8.25%; found:C 53.83%; H 5.36%; N 7.23%; S 8.30%.

EXAMPLE 63 N-Acetyldehydro-3-(2-thienyl)alanyl-L-tryptophan

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andL-tryptophan.

Melting point: 250° C.; yield: 43% of theory.

C₂₀ H₁₉ N₃ O₄ S; calculated: C 60.44%; H 4.82%; N 10.57%; S 8.07%;found: C 60.47%; H 4.88%; N 10.47%; S 8.23%.

EXAMPLE 64 N-Acetyldehydro-3-(2-thienyl)alanylglycine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone and glycine.

Melting point: 221°-223° C.; yield: 76.1% of theory.

C₁₁ H₁₂ N₂ O₄ S; calculated: C 49.25%; H 4.51%; N 10.44%; S 11.95%;found: C 49.14%; H 4.57%; N 10.45%; S 11.92%.

EXAMPLE 65N-Acetyldehydro-3-(2-thienyl)alanyl-2-(4-hydroxyphenyl)-D-glycine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone and2-(4-hydroxyphenyl)-D-glycine.

Melting point: 224°-226° C.; yield: 66.7% of theory.

C₁₇ H₁₆ N₂ O₅ S; calculated: C 56.66%; H 4.48%; N 7.77%; S 8.90%; found:C 56.62%; H 4.58%; N 7.63%; S 8.75%.

EXAMPLE 66 N-Benzoyldehydrophenylalanyl-L-leucylglycine4-methoxyphenylamide

is obtained from 2-phenyl-4-benzylidene-5(4H)oxazolone andL-leucylglycine 4-methoxyphenylamide.

Melting point: 211°-230° C.; yield: 50% of theory.

C₃₁ H₃₄ N₃ O₅ ; calculated: C 68.62%; H 6.32%; N 10.35%; found: C68.69%; H 6.33%; N 10.48%.

EXAMPLE 67N-Acetyldehydro-3-(2-thienyl)alanyl-2-(1,4-cyclohexanedien-1-yl)-D-glycine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone and2-(1,4-cyclohexanedien-1-yl)-D-glycine.

Melting point: 235°-240° C.; yield: 75.1% of theory.

C₁₇ H₁₈ N₂ O₄ S; calculated: C 58.94%; H 5.24%; N 8.09%; S 9.25%; found:C 58.79%; H 5.10%; N 7.93%; S 9.06%.

EXAMPLE 68 N-Acetyldehydro-3-(2-thienyl)alanyl-L-glutamic acid

is obtained from 2-methyl-4-(thenylidene)-5(4H)oxazolone and L-glutamicacid.

Melting point: 205° C. (decomposition); yield: 76.5% of theory.

C₁₄ H₁₆ N₂ O₆ S; calculated: C 49.40%; H 4.74%; N 8.23%; S 9.42%; found:C 49.61%; H 4.76%; N 8.16%; S 9.59%.

EXAMPLE 69 N-Acetyldehydro-3-(2-thienyl)alanyl-L-leucine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andL-leucine.

Melting point: 230° C.; yield: 89.5% of theory.

C₁₅ H₂₀ N₂ O₄ S; calculated: C 55.58%; H 6.21%; N 8.64%; S 9.88%; found:C 55.72%; H 6.27%; N 8.59%; S 9.87%.

EXAMPLE 70 N-Acetyldehydro-3-(2-thienyl)alanyl-L-phenylalanine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andL-phenylalanine.

Melting point: >230° C.; yield: 92.6% of theory.

C₁₈ H₁₈ N₂ O₄ S; calculated: C 60.34%; H 5.07%; N 7.82%; S 8.93%; found:C 60.37%; H 5.04%; N 7.81%; S 8.96%.

EXAMPLE 71 N-Acetyldehydro-3-(2-thienyl)alanyl-L-β-alanine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)-oxazolone andL-β-alanine.

Melting point: 186°-189° C.; yield: 78.5% of theory.

C₁₂ H₁₄ N₂ O₄ S; calculated: C 51.05%; H 5.00%; N 9.92%; S 11.36%;found: C 50.93%; H 5.07%; N 9.98%; S 11.44%.

EXAMPLE 72 N-Benzoyldehydrophenylalanylglycine

is obtained from 2-phenyl-4-benzylidene-5(4H)oxazolone and glycine.

Melting point: 233° C. (decomposition); yield: 88.7% of theory.

C₁₈ H₁₆ N₂ O₄ ; calculated: C 66.66%; H 4.97%; N 8.64%; found: C 66.87%;H 5.12%; N 8.54%.

EXAMPLE 73 N-Acetyldehydro-3-(2-thienyl)alanyl-DL-valine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andDL-valine.

Melting point: 229°-230° C. (decomposition); yield: 91.5% of theory.

C₁₄ H₁₈ N₂ O₄ S; calculated: C 54.18%; H 5.84%; N 9.03%; S 10.33%;found: C 54.01%; H 5.82%; N 9.02%; S 10.37%.

EXAMPLE 74N-(2-Thenoyl)dehydro-3-(2-thienyl)alanyl-2-(1,4-cyclohexanedien-1-yl)-D-glycine

is obtained from 2-(2-thienyl)-4-(2-thenylidene)-5(4H)oxazolone and2-(1,4-cyclohexanedien-1-yl)-D-glycine.

Melting point: 145°-155° C.; yield: 37.8% of theory.

C₂₀ H₁₈ N₂ O₄ S; calculated: C 57.95%; H 4.38%; N 6.76%; S 15.47%;found: C 57.82%; H 4.39%; N 6.57%; S 15.12%.

EXAMPLE 75 N-Acetyldehydro-3-(2-thienyl)alanyl-L-threonine

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andL-threonine.

Melting point: 262°-265° C. (decomposition); yield: 65% of theory.

C₁₃ H₁₆ N₂ O₅ S; calculated: C 49.99%; H 5.16%; N 8.97%; S 10.27%; foundC 49.61%; H 5.24%; N 8.89%; S 10.33%.

EXAMPLE 76 N-Acetyldehydro-3-(2-thienyl)alanyl-L-aspartic acid

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andL-aspartic acid.

Melting point: 232° C. (decomposition); yield: 62.5% of theory.

C₁₃ H₁₄ N₂ O₆ S; calculated: 47.85%; H 4.32%; N 8.58%; S 9.83%; found:47.70%; H 4.43%; N 8.45%; S 9.95%.

EXAMPLE 77 N-Benzoyldehydrophenylalanyl-L-tryptophan

is obtained from 2-phenyl-4-benzylidene-5(4H)oxazolone and L-tryptophan.

Yield: 38.9% of theory.

C₂₇ H₂₃ N₃ O₄ ; calculated: C 71.51%; H 5.11%; N 9.27%; found: C 71.45%;H 5.25%; N 9.12%.

EXAMPLE 78N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanyl-L-leucine

is obtained from2-(3-trifluoromethylphenyl)-4-(2-thenylidene)-5(4H)oxazolone andL-leucine.

Melting point: 100°-105° C.; yield: 100% of theory.

C₂₁ H₂₁ F₃ N₂ O₄ S; calculated: C 55.50%; H 4.66%; F 12.54%; N 6.16%;found: C 55.57%; H 4.74%; F 12.5%; N 6.10%.

EXAMPLE 79N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanyl-L-phenylalanine

is obtained from2-(3-trifluoromethylphenyl)-4-(2-thenylidene)-5(4H)oxazolone andL-phenylalanine.

Melting point: 103°-107° C.; yield: 88% of theory.

C₂₄ H₁₉ F₃ N₂ O₄ S; calculated: C 59.01%; H 3.92%; F 11.67%; N 5.74%;found: C 58.86%; H 4.01%; F 11.3%; N 5.72%.

EXAMPLE 80N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanylglycine

is obtained from2-(3-trifluoromethylphenyl)-4-(2-thenylidene)-5(4H)oxazolone andglycine.

Melting point: 91°-92° C.; yield: 81% of theory.

C₁₇ H₁₃ F₃ N₂ O₄ S; calculated: C 51.26%; H 3.29%; F 14.31%; N 7.03%; S8.04%; found: C 51.06%; H 3.45%; F 14.30%; N 6.94%; S 8.04%.

EXAMPLE 81 N-Trifluoroacetyldehydrophenylalanyl-L-tyrosine tert.-butylester

The reaction is carried out in dimethylformamide without NaOH.

Melting point: 182°-183° C.; [α]_(D) ²⁰ -29.7° (c=1, dimethylformamide);yield: 84% of theory.

C₂₄ H₂₅ F₃ N₂ O₅ ; calculated: C 60.24%; H 5.27%; F 11.91%; N 5.86%;found: C 60.30%; H 5.30%; F 11.91%; N 5.93%.

EXAMPLE 82N-Acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinetert.-butyl ester

is obtained from2-[1-acetamido-3-(2-thienyl)vinyl]-4-(2-thenylidene)-5(4H)oxazolone andL-tyrosine tert.-butyl ester analogously to Example 81.

Melting point: 158° C.; yield: 94% of theory.

C₂₉ H₃₁ N₃ O₆ S₂ ; calculated: C 59.88%; H 5.37%; N 7.22%; S 11.03%;found: C 60.01%; H 5.41%; N 7.15%; S 11.08%.

EXAMPLE 83N-Acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinebenzyl ester

is obtained from2-[1-acetamido-2-(2-thienyl)vinyl]-4-(2-thenylidene)-5(4H)oxazolone andL-tyrosine benzyl ester analogously to Example 81.

Melting point: 130° C.; yield: 83% of theory.

C₃₂ H₂₉ N₃ O₆ S₂ ; calculated: C 62.42%; H 4.75%; N 6.82%; S 10.42%;found: C 62.52%; H 4.68%; N 6.83%; S 10.40%.

EXAMPLE 84N-Acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinemethyl ester

is obtained from2-[1-acetamido-2-(2-thienyl)vinyl]-4-(2-thenylidene)-5-(4H)oxazolone andL-tyrosine methyl ester analogously to Example 81.

Melting point: 155° C.; yield: 96% of theory.

C₂₆ H₂₅ N₃ O₆ S₂ ; calculated: C 57.86%; H 4.67%; N 7.79%; S 11.89%;found: C 58.08%; H 4.79%; N 7.75%; S 11.88%.

EXAMPLE 85 N-Acetyldehydro-3-(2-thienyl)alanyl-N-methyl-L-tyrosinemethyl ester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone andN-methyl-L-tyrosine methyl ester analogously to Example 81.

Melting point: 102° C.; yield: 38.9% of theory.

C₂₀ H₂₂ N₂ O₅ S.H₂ O; calculated: C 58.38%; H 5.63%; N 6.81%; S 7.79%;found: C 58.28%; H 5.59%; N 6.89%; S 8.15%.

EXAMPLE 86 N-Acetyldehydro-3-(3-thienyl)alanyl-N-methyl-L-tyrosine

is obtained from the above compound by boiling with NaOH. Melting point:150°-170° C.; yield: 72.6% of theory.

C₁₉ H₂₀ N₂ O₅ S; calculated: C 58.75%; H 5.19%; N 7.21%; S 8.25%; found:C 58.62%; H 5.36%; N 7.08%; S 8.35%.

EXAMPLE 87 N-Acetyldehydro-3-(3-nitro-4-hydrophenyl)alanyl-L-tyrosinetert.-butyl ester

is obtained from2-methyl-4-(3-nitro-4-acetoxybenzylidene)-5(4H)oxazolone and L-tyrosinetert.-butyl ester analogously to Example 81.

Melting point: 148°-151° C.; yield: 45.5% of theory.

C₂₄ H₂₇ N₃ O₈ ; calculated: C 59.37%; H 5.61%; N 8.66%; found: C 59.43%;H 5.71%; N 8.54%.

EXAMPLE 88 N-Acetyldehydro-3-(3-nitro-4-hydroxyphenyl)alanyl-L-tyrosine

is obtained from the above compound by stirring with trifluoroaceticacid.

Melting point: 145° C.; yield: 93% of theory.

C₂₁ H₂₂ N₃ O₈ ; calculated: C 56.76%; H 4.99%; N 9.24%; found: C 56.88%;H 5.09%; N 9.31%.

EXAMPLE 89 N-Benzoyldehydro-3-(4-pyridyl)alanyl-L-tyrosine methyl ester

is obtained from 2-phenyl-4-(4-pyridinylmethylene)-5(4H)-oxazolone andL-tyrosine methyl ester analogously to Example 81.

Melting point: 155°-160° C.; yield: 33.7% of theory.

C₂₅ H₂₃ N₃ O₅.H₂ O; calculated: C 66.07%; H 5.32%; N 9.25%; found: C66.17%; H 5.59%; N 9.25%.

EXAMPLE 90 N-benzoyldehydro-3-(4-pyridyl)alanyl-L-tyrosine

is obtained from the above compound by boiling with dilute sodiumhydroxide solution.

Melting point: 162°-166° C.; yield: 54.3% of theory.

C₂₄ H₂₁ N₃ O₅ ; calculated: C 66.81%; H 4.91%; N 9.74%; found: C 66.63%;H 5.13%; N 9.77%.

EXAMPLE 91 N-(4-Nitrophenyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinemethyl ester

Melting point: 218°-222° C.; yield: 55.7% of theory.

C₂₅ H₂₃ N₃ O₇ S; calculated: C 58.93%; H 4.55%; N 8.25%; S 6.29%; found:C 58.82%; H 4.55%; N 8.13%; S 6.11%.

EXAMPLE 92 N-(4-Nitrophenyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine

is obtained from the above compound by boiling with dilute sodiumhydroxide solution.

Melting point: 161°-166° C.; yield: 41.6% of theory.

C₂₄ H₂₁ N₃ O₇ S; calculated: C 58.17%; H 4.27%; N 8.48%; S 6.47%; found:C 58.26%; H 4.44%; N 8.45%; S 6.63%.

EXAMPLE 93N-Acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosinetert.-butyl ester

is obtained from2-[1-acetamido-2-(2-thienyl)vinyl]-4-(2-thenylidine)-5(4H)oxazolone andL-tyrosine tert.-butyl ester analogously to Example 81.

Melting point: 158° C. (decomposition); yield: 94% of theory.

C₂₉ H₃₁ N₃ O₆ S₂ ; calculated: C 59.88%; H 5.375; N 7.22%; S 11.03%;found: C 60.01%; H 5.41%; N 7.15%; S 11.08%.

EXAMPLE 94N-Acetyldehydro-3-(2-thienyl)alanyl-3-(2-thienyl)dehydroalanyl-L-tyrosine

is obtained from the above compound by adding glacial acetic acid/HCl.

Melting point: 189° C. (decomposition); yield: 88% of theory.

C₂₅ H₂₃ N₃ O₆ S₂ ; calculated: C 57.13%; H 4.91%; N 7.99%; S 12.20%;found: C 56.90%; H 4.63%; N 7.92%; S 12.04%.

EXAMPLE 95 N-Benzoyldehydroisoleucyl-L-tyrosine methyl ester

is obtained from 2-phenyl-4-(1-methylpropylidene)-5(4H)-oxazolone andtyrosine methyl ester analogously to Example 81.

Melting point: 163°-165° C.; yield: 35.5% of theory.

C₃₃ H₂₆ N₂ O₅ ; calculated: C 67.30%; H 6.38%; N 6.83%; found: C 67.23%;H 6.35%; N 6.82%.

EXAMPLE 96 N-(2-Thienyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinetert. butyl ester

is obtained from 2-(2-thienylmethyl)-4-(2-thenylidene)-5(4H)-oxazoloneand L-tyrosine tert.-butyl ester analogously to Example 81.

Melting point: 105° C.; yield: 85% of theory.

C₂₆ H₂₈ N₂ O₅ S₂ ; calculated: C 60.91%; H 5.50%; N 5.47%; S 12.51%;found: C 61.02%; H 5.57%; N 5.60%; S 12.36%.

EXAMPLE 97 N-(2-Thienyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine

is obtained from the above compound by adding glacial aceticacid/hydrochloric acid.

Melting point: 110° C.; yield: 95% of theory.

C₂₂ H₂₀ N₂ O₅ S₂ ; calculated: C 57.88%; H 4.41%; N 6.14%; S 14.05%;found: C 57.64%; H 4.52%; N 6.06%; S 13.90%.

EXAMPLE 98 N-(2-Thienyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinebenzyl ester

is obtained from 2-(2-thienylmethyl)-4-(2-thenylidene)-5(4H)-oxazoloneand L-tyrosine benzyl ester analogously to Example 81. Melting point:95° C.; yield: 83% of theory.

C₂₉ H₂₆ N₂ O₅ S₂ ; calculated: C 63.71%; H 4.79%; N 5.13%; S 11.74%;found: C 63.85%; H 4.80%; N 5.06%; S 11.69%.

EXAMPLE 99 N-(2-Thienyl)acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinemethyl ester

is obtained from 2-(2-thienylmethyl)-4-(2-thenylidene)-5(4H)-oxazoloneand L-tyrosine methyl ester analogously to Example 81. Melting point:200° C. (decomposition); yield: 80% of theory.

C₂₃ H₂₂ N₂ O₅ S₂ ; calculated: C 58.70%; H 4.71%; N 5.95%; S 13.63%;found: C 58.79%; H 4.76%; N 5.95%; S 13.50%.

EXAMPLE 100 N-Trifluoroacetyldehydrophenylalanyl-L-tyrosine

Melting point: 165°-175° C.; [α]_(D) ²⁰ -57.4° (c=1; dimethylformamide;yield: 91% of theory.

C₂₀ H₁₇ F₃ N₂ O₅ ; calculated: C 56.87%; H 4.06%; F 13.5%; N 6.63%;found: C 56.92%; H 4.05%; F 13.4%; N 6.61%.

EXAMPLE 101 N-Phenacetyldehydro-3-(2-thienyl)alanyl-L-tyrosinetert.-butyl ester

is prepared in dimethylformamide without NaOH.

Melting point: 110°-120° C. (crude product); yield: 51.5% of theory.

This compound was further processed by stirring for 1/2 an hour withtrifluoroacetic acid to give

N-Phenacetyldehydro-3-(2-thienyl)alanyl-L-tyrosine

Melting point: 135°-140° C. (decomposition); [α]_(D) ²⁰ -41°; yield: 49%of theory.

C₂₄ H₂₂ N₂ O₅ S; calculated: C 63.98%; H 4.92%; N 6.22%; S 7.12%; found:C 63.79%; H 4.82%; N 6.29%; S 7.07%.

EXAMPLE 102 N-Phenacetyldehydro-3-(2-thienyl)alanyl-L-leucine

N-Phenacetyldehydro-3-(2-thienyl)alanyl-L-leucine methyl ester is formedfrom 4.05 g (0.015 mol) of 2-benzyl-4-(2-thenylidene)-5(4H)oxazolone and3 g (0.0165 mol) of L-leucine methyl ester hydrochloride indimethylformamide in the presence of triethylamine by stirring themixture for two hours and allowing it to stand for twelve hours,diluting it with water, extracting it with ether, washing the etherextract with dilute citric acid and evaporating the dried ethersolution. Melting point: 160°-161° C.; yield: 4.75 g (76.3% of theory).

4.66 g (0.011 mol) of the above compound were dissolved in 50 ml oftetrahydrofurane at 0° C., the solution was stirred with 11 ml of N NaOHat room temperature for two hours, the reaction solution was extractedwith chloroform and the aqueous phase was acidified and then extractedwith chloroform. 3.8 g (63.3% of theory) ofN-phenacetyldehydro-3-(2-thienyl)-alanyl-L-leucine of melting point207°-208° C. were obtained. [α]_(D) ²⁰ -45.2°.

C₂₁ H₂₄ N₂ O₄ S; calculated: C 62.98%; H 6.04%; N 6.99%; S 8.00%; found:C 62.92%; H 6.02%; N 7.03%; S 7.92%.

EXAMPLE 103 N-Benzoyldehydrophenylalanyl-L-leucylglycine anilide

is obtained from 2-phenyl-4-benzylidene-5(4H)oxazolone andL-leucylglycine anilide analgously to Example 102.

Melting point: 179°-180° C.; yield: 35.3% of theory.

C₃₀ H₃₂ N₄ O₄ ; calculated: C 70.29%; H 6.29%; N 10.93%; found: C69.44%; H 6.41%; N 10.82%.

EXAMPLE 104 N-Benzoyldehydrophenylalanyl-L-prolyl-L-leucylglycineanilide

is obtained from 2-phenyl-4-benzylidene-5(4H)oxazolone andL-prolyl-L-leucylglycine amide.

Melting point: 192° C.; yield: 98% of theory.

C₃₅ H₃₉ N₅ O₅ ; calculated: C 68.95%; H 6.45%; N 11.49%; found: C69.03%; H 6.42%; N 11.45%.

EXAMPLE 105 N-Acetyldehydro-3-(2-thienyl)alanyl-2-methylalanine methylester

is obtained from 2-methyl-4-(2-thenylidene)-5(4H)oxazolone and2-methylalanine methyl ester analogously to Example 102.

Melting point: 181°-182° C.; yield 69% of theory.

C₁₄ H₁₈ N₂ O₄ S; calculated: C 54.18%; H 5.85%; N 9.03%; S 10.33%;found: C 54.32%; H 5.83%; N 9.12%; S 10.51%.

EXAMPLE 106 N-Acetyldehydro-3-(2-thienyl)alanyl-2-methylalanine

is obtained from the above compound by boiling with dilute sodiumhydroxide solution.

Melting point: 241° C. (decomposition); yield: 94% of theory.

C₁₃ H₁₆ N₂ O₄ S; calculated: C 52.69%; H 5.44%; N 9.45%; S 10.82%;found: C 52.64%; H 5.37%; N 9.47%; S 10.76%.

EXAMPLE 107 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine

Melting point: 135° C. (ill-defined); yield: 41.2% of theory.

C₂₃ H₂₀ N₂ O₅ S; calculated: C 63.29%; H 4.62%; N 6.43%; S 7.34%; found:C 63.25%; H 4.67%; N 6.37%; S 7.38%.

EXAMPLE 108N-Benzoyldehydro-3-(2-thienyl)alanyl-L-(p-nitrophenyl)alanine

Melting point: 125° C. (ill-defined); [α]_(D) ²⁰ -67.3°; yield: 60% oftheory.

C₂₃ H₁₉ N₃ O₆ S; calculated: C 59.35%; H 4.11%; N 9.03%; S 6.89%; found:C 59.39%; H 4.36%; N 9.01%; S 6.71%.

EXAMPLE 109 N-Nicotinoyldehydro-3-(2-thienyl)alanyl-L-tyrosine

Melting point: 160° C. (ill-defined); [α]_(D) ²⁰ -8.35°; yield: 50% oftheory.

C₂₂ H₁₉ N₃ O₅ S; calculated: C 60.40%; H 4.38%; N 9.60%; S 7.33%; found:C 60.57%; H 4.58%; N 9.75%; S 7.32%.

EXAMPLE 110N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanyl-L-tyrosine

Melting point: 125° C. (ill-defined); [α]_(D) ²⁰ -8.9°; yield: 48% oftheory.

C₂₄ H₁₉ F₃ N₂ O₅ S; calculated: C 57.14%; H 3.80%; F 11.30%; N 5.55%; S6.36%; found: C 56.95%; H 3.81%; F 11.40%; N 5.45%; S 6.45%.

EXAMPLE 111N-Nicotinoyldehydro-3-(2-thienyl)alanyl-L-(p-nitrophenyl)alanine

Melting point: 197° C. (decomposition); [α]_(D) ²⁰ -98°; yield: 75% oftheory.

C₂₂ H₁₈ N₄ O₆ S; calculated: C 56.64%; H 3.89%; N 12.01%; S 6.87%;found: C 56.55%; H 3.91%; N 12.05%; S 6.89%.

EXAMPLE 112 N-Benzoyl-3-methyl-3-(2-thienyl)dehydroalanyl-L-tyrosine

Melting point: 128° C; [α]_(D) ²⁰ +15.6°; yield: 66.7% of theory.

C₂₄ H₂₂ N₂ O₅ S; calculated: C 63.98%; H 4.92%; N 6.22%; S 7.12%; found:C 64.14%; H 4.93%; N 6.34%; S 7.03%.

EXAMPLE 113 N-acetyldehydro-3-(2-thienyl)alanyl-D-tyrosine

Melting point: 221°-222° C.; [α]_(D) ²⁰ +36.8°; yield: 51.49% of theory.

C₁₈ H₁₈ N₂ O₅ S; calculated: C 57.74%; H 4.85%; N 7.48%; S 8.56%; found:C 57.83%; H 4.89%; N 7.44%; S 8.67%.

EXAMPLE 114 N-Cinnamoyldehydrophenylalanylglycine

Melting point: 159°-160° C.; yield: 75% of theory.

C₂₀ H₁₈ N₂ O₄.H₂ O; calculated: C 65.20%; H 5.47%; N 7.61; found: C65.27%; H 5.32%; N 7.76%.

EXAMPLE 115 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-phenylalanine

Melting point: 100° C.; [α]_(D) ²⁰ -4.8° (c=1; dimethylsulphoxide);yield: 80% of theory.

C₂₃ H₂₀ N₂ O₄ S; calculated: C 65.70%; H 4.79%; N 6.66%; S 7.63%; found:C 65.64%; H 5.01%; N 6.50%; S 7.41%.

EXAMPLE 116 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-leucine

Melting point: 110°-120° C.; [α]_(D) ²⁰ +24.8° (c=1;dimethylsulphoxide); yield: 90% of theory.

C₂₀ H₂₂ N₂ O₄ S; calculated: C 62.16%; H 5.74%; N 7.25%; S 8.29%; found:C 62.19%; H 5.84%; N 7.20%; S 8.23%.

EXAMPLE 117 N-Acetyldehydro-3-(2-thienyl)-L-phenylalanine

Melting point: >230° C.; [α]_(D) ²⁰ -68.8° (c=1; dimethylsulphoxide);yield: 90% of theory.

C₁₈ H₁₈ N₂ O₄ S; calculated: C 60.32%; H 5.07%; N 7.82%; S 8.93%; found:C 60.37%; H 5.04%; N 7.81%; S 8.96%.

EXAMPLE 118 N-Benzoyl-3-methylphenyldehydroalanyl-L-leucine

Melting point: 102°-104° C.; [α]_(D) ²⁰ -8.1°; yield: 75% of theory.

C₂₃ H₂₆ N₂ O₄ ; calculated: C 70.03%; H 6.64%; N 7.10%; found: C 69.29%;H 6.48%; N 7.02%.

EXAMPLE 119 N-Cinnamoyldehydrophenylalanyl-L-tyrosine

Melting point: 172°-174° C.; [α]_(D) ²⁰ -24°; yield: 30% of theory.

C₂₇ H₂₄ N₂ O₅ ; calculated: C 71.04%; H 5.3%; N 6.14%; found: C 70.85%;H 5.39%; N 6.16%.

EXAMPLE 120 N-Acetyldehydro-3-(2-thienyl)alanine

Melting point 230° C. (decomposition). Preparation of the literature.

EXAMPLE 121 N-Acetyldehydro-3-(2-thienyl)alanyl-L-leucine

Melting point: >230° C.; [α]_(D) ²⁰ -11.0° (c=1; dimethylsulphoxide);yield: 90% of theory.

C₁₅ H₂₀ N₂ O₄ S: calculated: C 55.54%; H 6.21%; N 8.64%; S 9.88%; found:C 55.72%; H 6.27%; N 8.59%; S 9.87%.

EXAMPLE 122 N-Benzoyldehydroisoleucyl-L-tyrosine

Melting point: 107° C.; [α]_(D) ²⁰ -12.1°; yield: 31.5% of theory.

C₂₂ H₂₄ N₂ O₅ ; calculated: C 66.65%; H 6.10%; N 7.07%; found: C 66.57%;H 6.17%; N 6.90%.

EXAMPLE 123 N-Benzoyl-3-methyl-3-cinnamenyldehydroalanyl-L-tyrosine

Melting point: 130° C.; [α]_(D) ²⁰ -5.5°; yield: 96% of theory.

C₂₈ H₂₆ N₂ O₅ ; calculated: C 71.47%; H 5.57%; N 5.95%; found: C 71.60%;H 5.57%; N 5.87%.

EXAMPLE 124N-Acetyldehydrophenylalanyldehydro(3-chlorophenyl)alanyl-L-tyrosine

is obtained by aminolysis of4-(3-chlorobenzylidene)-2-(1-acetamido-2-phenylethylene)-5(4H)-oxazolonewith L-tyrosine.

Melting point: 191°-193° C.; [α]_(D) ²⁰ -154.3° (c=1;dimethylformamide); yield: 78.5% of theory.

C₂₉ H₂₆ ClN₃ O₆ ; calculated: C 63.56%; H 4.78%; Cl 6.47%; N 7.67%;found: C 63.69%; H 4.76%; Cl 6.54%; N 7.70%.

EXAMPLE 125 N-Acetyldehydrophenylalanyldehydrotyrosine

6.09 g (0.0175 mol) of2-(1-acetamido-2-phenylethylene)-4-(4-hydroxybenzylidene)-5(4H)-oxazoloneare mixed with 46.9 ml of N NaOH and 40 ml of acetone and the mixture isstirred at room temperature for three hours. After distilling off theacetone, acidifying the aqueous reaction solution with 47.6 ml of N HCland recrystallising the precipitate, which has separated out and beenfiltered off, from ethanol/petroleum ether, 3.75 g (58.6% of theory) ofN-acetyldehydrophenylalanyldehydrotyrosine of melting point 202°-206° C.are obtained. Preparation in the literature.

The following compounds were prepared analogously from the correspondingoxazolones:

EXAMPLE 126 N-Acetyldehydrophenylalanyldehydro-(p-nitrophenyl)alanine

Melting point: 182° C.; yield: 56.4% of theory.

C₂₀ H₁₇ N₃ O₆ ; calculated: C 60.76%; H 4.33%; N 10.63%; found: C60.86%; H 4.51%; N 10.46%.

EXAMPLE 127 N-Acetyldehydrophenylalanyldehydro(4-chlorophenyl)alanine

Melting point: 177° C.; yield: 60.9% of theory.

C₂₀ H₁₇ ClN₂ O₄ ; calculated; C 62.42%; H 4.45%; N 7.28%; Cl 9.21%;found: C 62.49%; H 4.47%; N 7.37%; Cl 9.24%.

EXAMPLE 128 N-Acetyldehydrophenylalanyldehydro(p-fluorophenyl)alanine

Melting point: 172° C.; yield: 65.27% of theory.

C₂₀ H₁₇ FN₂ O₄.H₂ O; calculated: C 62.17%; H 4.96%; F 4.92%; N 7.25%;found: C 62.30%; H 4.94%; F 4.70%; N 7.25%.

EXAMPLE 129N-Acetyldehydrophenylalanyldehydro(4-dimethylaminophenyl)alanine

Melting point: 153°-155° C.; yield: 36.2% of theory.

C₂₂ H₂₃ N₃ O₄ ; calculated: C 67.16%; H 5.89%; N 10.68%; found: C67.03%; H 6.00%; N 10.52%.

EXAMPLE 130 N-Acetyldehydrophenylalanyldehydro(3-chlorophenyl)alanine

Melting point: 183° C.; yield: 88.4% of theory. C₂₀ H₁₇ ClN₂ O₄ ;calculated: C 62.42%; H 4.45%; Cl 9.21%; N 7.28%; found: C 62.54%; H4.45%; Cl 9.23%; N 7.18%.

In the following examples, the reaction was carried out intetrahydrofurane without NaOH.

EXAMPLE 131 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine methyl ester

Melting point: 120° C. (ill-defined); [α]_(D) ²⁰ -4.6°; yield: 95% oftheory.

C₂₄ H₂₂ N₂ O₅ S; calculated: C 63.98%; H 4.92%; N 6.22%; S 7.12%; found:C 63.78%; H 4.93%; N 6.07%; S 7.02%.

EXAMPLE 132 N-Acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine methyl ester

Melting point: 243°-245° C.; [α]_(D) ²⁰ -78.1° (c=1;dimethylsulphoxide); yield: 65% of theory.

C₁₉ H₂₀ N₂ O₅ S; calculated: C 58.75%; H 5.19%; N 7.21%; S 8.26%; found:C 58.45%; H 5.35%; N 7.17%; S 8.47%.

EXAMPLE 133 N-Benzoyldehydro-3-(2-thienyl)alanyl-l-tyrosine benzyl ester

is obtained from the acid and benzyl alcohol by heating to 80° C. for1/2 an hour in the presence of hydrogen chloride.

Melting point: 95° C. (ill-defined); [α]_(D) ²⁰ -2.0°; yield: 79% oftheory.

C₃₀ H₂₆ N₂ O₅ S; calculated: C 68.42%; H 4.98%; N 5.32%; S 6.09%; found:C 68.42%; H 4.96%; N 5.30%; S 6.02%.

EXAMPLE 134 The salt of N-acetyldehydro-3-(2-thienyl)alanine withmorpholine

To 1.5 g of the dehydroamino acid, three times the amount of morpholineis added and the mixture is diluted with methanol and evaporated todryness.

Melting point: 173° C. (decomposition); yield: 89% of theory.

C₁₃ H₁₈ N₂ O₄ S; calculated: C 52.4%; H 6.0%; N 9.4%; S 10.7%; found: C52.8%; H 6.2%; N 9.4%; S 11.1%.

The following compounds are prepared analogously to Example 134:

EXAMPLE 135 The salt of N-acetyldehydro-3-(2-thienyl)alanine withmethylamine

Melting point: 178° C.; yield: 99% of theory.

C₁₀ H₁₄ N₂ O₃ S; calculated: C 49.57%; H 5.82%; N 11.56%; S 13.24%;found: C 49.74%; H 5.92%; N 11.60%; S 13.23%.

EXAMPLE 136 The salt of N-acetyldehydro-3-(2-thienyl)alanine with1,1-dimethylproparglyamine

Melting point: 221° C. (decomposition); yield: 99% of theory.

(C₁₄ H₁₈ N₂ O₃ S; calculated: C 57.12%; H 6.16%; N 9.52%; S 10.89%;found: C 57.24%; H 6.21%; N 9.68%; S 11.06%.

EXAMPLE 137 The lithium salt of N-acetyldehydro-3-(2-thienyl)alanine

Melting point: >300° C.; yield: 66.08% of theory.

C₉ H₈ LiNO₃ S; calculated: C 49.77%; H 3.71%; N 6.45%; S 14.76%; Li3.21%; found: C 49.79%; H 3.92%; N 6.30%; S 14.45%; Li 3.35%.

EXAMPLE 138 The salt of N-acetyladehydro-3-(2-thienyl)alanyl-L-tyrosinewith morpholine

Melting point: 136°-150° C.; yield: 69.40% of theory.

C₂₂ H₂₇ N₃ O₆ S; calculated: C 57.25%; H 5.90%; N 9.11%; S 6.95%; found:C 56.54%; H 6.14%; N 8.85%; S 6.42%.

EXAMPLE 139 The salt of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinewith piperidine

Melting point: 184°-186° C.; yield: 58.80% of theory.

C₂₃ H₂₉ N₃ O₅ S; calculated: C 60.11%; H 6.36%; N 9.14%; S 6.98%; found:C 60.29%; H 6.27%; N 9.33%; S 7.17%.

EXAMPLE 140 The salt of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinewith ethylenediamine

Melting point: 148°-158° C.; yield: 98.9% of theory.

C₃₈ H₄₄ N₆ O₁₀ S₂ ; calculated: C 56.42%; H 5.48%; N 10.39%; S 7.93;found: C 56.38%; H 5.64%; N 10.26%; S 7.81%.

EXAMPLE 141 The salt of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinewith triethanolamine

Melting point: 125°-130° C.; yield: 84.1% of theory.

C₂₄ H₃₃ N₃ O₈ S; calculated: C 55.05%; H 6.35%; N 8.03%; S 6.12%; found:C 54.77%; H 6.30%; N 7.93%; S 6.00%.

EXAMPLE 142 The salt of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinewith DL-canavanine

Melting point: 165°-173° C.; yield: 90.9% of theory.

C₂₃ H₃₀ N₆ O₈ S; calculated: C 50.17%; H 5.49%; N 15.27%; S 5.81%;found: C 50.02%; H 5.62%; N 15.35%; S 5.67%.

EXAMPLE 143 The salt of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinewith L-arginine

Melting point: 125°-140° C.; yield: 79.3% of theory.

C₂₄ H₃₂ N₆ O₇ S; calculated: C 52.54%; H 5.88%; N 15.32%; S 5.85%;found: C 52.44%; H 6.00%; N 15.31; S 5.10%.

EXAMPLE 144 The salt of N-acetyldehydro-3-(2-thienyl)alanyl-L-tyrosinewith L-lysine

Melting point: 174°-182° C.; yield: 96.1% of theory.

C₂₄ H₃₂ N₄ O₇ S; calculated: C 55.37%; H 6.20%; N 10.76%; S 6.16%;found: C 55.22%; H 6.41%; N 10.87%; S 6.04%.

The amides which follow were prepared from the corresponding methylesters by allowing a mixture of the esters and the corresponding amines(1 mol of ester per 8 mols of amine) in methanol or tetrahydrofurane tostand and working up the mixture by evaporation and purification onsilica gel (reaction time 3-340 hours).

EXAMPLE 145 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine amide

Melting point: 210° C.; [α]_(D) ²⁰ -62.0°; yield: 86% of theory.

C₂₃ H₂₁ N₃ O₄ S; calculated: C 63.43%; H 4.86%; N 9.65%; S 7.36%; found:C 63.25%; H 4.96%; N 9.59%; S 7.38%.

EXAMPLE 146 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosineN'-hexylamide

Melting point: 115° C. (ill-defined); [α]_(D) ²⁰ -63.4°; yield: 80% oftheory.

C₂₉ H₃₃ N₃ O₄ S; calculated: C 67.03%; H 6.40%; N 8.09%; S 6.17%; found:C 67.22%; H 6.51%; N 8.19%; S 6.08%.

EXAMPLE 147 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosineN'-methylamide

Melting point: 145° C. (ill-defined); [α]_(D) ²⁰ -61.7°; yield: 90.2% oftheory.

C₂₄ H₂₃ N₃ O₄ S;

calculated: C 64.12%; H 5.16%; N 9.35%; S 7.13%; found: C 64.04%; H4.99%; N 9.42%; S 7.07%.

EXAMPLE 148 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosineN'-cyclohexylamide

Melting point: 110° C. (ill-defined); [α]_(D) ²⁰ -50.9°; yield: 44% oftheory.

C₂₉ H₃₁ N₃ O₄ S; calculated: C 67.29%; H 6.04%; N 8.12%; S 6.19%; found:C 67.38%; H 6.33%; N 8.09%; S 5.88%.

EXAMPLE 149 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosineN',N'-dimethylamide

Melting point: 130° C. (ill-defined); [α]_(D) ²⁰ -2.2°; yield: 13% oftheory.

C₂₅ H₂₅ N₃ O₄ S; calculated: C 64.77%; H 5.44%; N 9.06%; S 6.92%; found:C 64.64%; H 5.41%; N 9.06%; S 6.77%.

EXAMPLE 150 N-benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine morpholide

Melting point: 120° C. (ill-defined); [α]_(D) ²⁰ -0.7°; yield: 22% oftheory.

C₂₇ H₂₇ N₃ O₅ S; calculated: C 64.14%; H 4.38%; N 8.32%; S 6.34%; found:C 63.92%; H 5.53%; N 8.27%; S 6.09%.

EXAMPLE 151 N-Benzoyldehydro-3-(2-thienyl)-L-tyrosine-N'-benzylamide

Melting point: 133° C; [α]_(D) ²⁰ -69.83°; yield: 68% of theory.

C₃₀ H₂₇ N₃ O₄ S; calculated: C 63.55%; H 5.18%; N 7.99%; S 6.10%; found:C 63.65%; H 5.25%; N 8.13%; S 6.03%.

EXAMPLE 152 N-Acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine2-dimethylaminopropylamide

Melting point: 177°-179° C. (decomposition); yield: 63% of theory.

C₂₃ H₃₀ N₄ O₄ S; calculated: C 60.24%; H 6.59%; N 12.22%; S 6.99%;found: C 60.39%; H 6.75%; N 12.40%; S 6.89%.

EXAMPLE 153 N-Acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine amide

Melting point: 147° C.; yield: 79% of theory.

C₁₈ H₁₉ N₃ O₄ S; calculated: C 57.89%; H 5.13%; N 11.25%; S 8.59%;found: C 57.75%; H 5.20%; N 11.09%; S 8.53%.

EXAMPLE 154 N-Acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine methylamide

Melting point: 225° C.; yield: 50% of theory.

C₁₉ H₂₁ N₃ O₄ S; calculated C 58.90%; H 5.46%; N 10.85%; S 8.27%; found:C 58.90%; H 5.47%; N 10.85%; S 8.30%.

EXAMPLE 155 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine6-aminohexylamide

Melting point: 122° C.; yield: 51.4% of theory.

C₂₉ H₃₄ N₄ O₄ S; calculated: C 65.14%; H 6.41%; N 10.48%; S 6.00%;found: C 65.04%; H 6.42%; N 10.45%; S 6.10%.

EXAMPLE 156 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine4-aminobutylamide

Melting point: 126° C.; yield: 70% of theory.

C₂₇ H₃₀ N₄ O₄ S; calculated: C 64.00%; H 5.96%; N 11.06%; S 6.32%;found: C 64.28%; H 5.98%; N 10.84%; S 6.19%.

EXAMPLE 157 N-Acetyldehydro-3-(2-thienyl)alanyl-L-tyrosine hydrazide

Melting point: 240° C. (decomposition); yield: 35.3% of theory.

C₁₈ H₂₀ N₄ O₄ S; calculated: C 55.66%; H 5.19%; N 14.42%; S 8.25%;found: C 55.58%; H 5.28%; N 14.56%; S 8.34%.

EXAMPLE 158 N-Benzoyldehydro-3-(2-thienyl)alanyl-L-tyrosine hydrazide

Melting point: 135° C.; yield: 82.2% of theory.

C₂₃ H₂₂ N₄ O₄ S; calculated: C 61.32%; H 4.92%; N 12.44%; S 7.11%;found: C 61.12%; H 5.02%; N 12.38%; S 7.26%.

If instead of sodium hydroxide a corresponding amine is used, thefollowing compounds are formed from the corresponding 5(4H)oxazolones:

EXAMPLE 159 N-Acetyldehydro-3-(2-thienyl)alanine N'-methylamide

Melting point: 183° C.; yield: 89% of theory.

C₁₀ H₁₂ N₂ O₂ S; calculated: C 53.55%; H 5.39%; N 12.49%; S 14.30%;found: C 53.66%; H 5.52%; N 12.52%; S 14.23%.

EXAMPLE 160 N-Acetyldehydro-3-(2-thienyl)alanineN'-1,1-dimethyl-2-propinylamide

Melting point: 197°-200° C.; yield: 36.2% of theory.

C₁₄ H₁₆ N₂ O₂ S; calculated: C 60.85%; H 5.84%; N 10.14%; S 11.60%;found C 60.64%; H 6.06%; N 10.08%; S 11.38%.

EXAMPLE 161 N-Acetyldehydro-3-(2-thienyl)alanine morpholide

Melting point: 159° C.; yield: 82.7% of theory.

C₁₃ H₁₆ N₂ O₃ S; calculated: C 55.69%; H 5.75%; N 9.99%; S 11.44%;found: C 55.80%; H 5.73%; N 10.09%; S 11.22%.

EXAMPLE 162 N-Cinnamoyldehydroalanine N'-methylamide

Melting point: 114°-118° C.; yield: 70% of theory.

C₁₉ H₁₈ N₂ O₂ ; calculated: C 74.5%; H 5.9%; N 9.1%; found: C 74.4%; H6.0%; N 9.0%.

EXAMPLE 163 N-Cinnamoyldehydroalanine 1,1-dimethyl-2-propinylamide

Melting point: 200°-203° C.; yield: 40% of theory.

C₂₃ H₂₂ N₂ O₂ ; calculated: C 77.1%; H 6.2%; N 7.8%; found: C 77.1%; H6.2%; N 8.0%.

EXAMPLE 164 N-Cinnamoyldehydroalanine morpholide

Melting point: 179°-182° C.; yield: 50% of theory.

C₂₂ H₂₂ N₂ O₃ ; calculated: C 72.9%; H 6.1%; N 7.7%; found: C 72.8%; H6.2%; N 7.5%.

EXAMPLE 165 N-Ethoxyacetyldehydro-3-(2-thienyl)alanine4-methylpiperazide

Melting point: 95°-97° C.; yield: 71.4% of theory.

C₁₆ H₂₃ N₃ O₃ S; calculated: C 56.95%; H 6.87%; N 12.45%; S 9.50; found:C 56.79%; H 6.94%; N 12.44%; S 9.56%.

EXAMPLE 166 N-Ethoxyacetyldehydro-3-(2-thienyl)alanine anilide

Melting point: 158°-159° C. yield: 97.9% of theory.

C₁₇ H₁₈ N₂ O₃ S; calculated: C 61.80%; H 5.49%; N 8.48%; S 9.70%; found:C 61.90%; H 5.48%; N 8.48%; S 9.65%.

EXAMPLE 167 N-Ethoxyacetyldehydro-3-(2-thienyl)alanine cyclohexylamide

Melting point: 142°144° C.; yield: 72% of theory.

C₁₇ H₂₄ N₂ O₃ S; calculated: C 60.69%; H 7.19%; N 8.32%; S 9.53%; found:C 60.27%; H 7.25%; N 8.32%; S 9.42%.

EXAMPLE 168 N-Ethoxyacetyldehydro-3-(2-thienyl)alanine amide

Melting point: 145°-147° C.; yield: 50.6% of theory.

C₁₁ H₁₄ N₂ O₃ S; calculated: C 51.95%; H 5.55%; N 11.01%; S 12.62%;found: C 51.92%; H 5.50%; N 10.86%; S 12.66%.

EXAMPLE 169 N-Crotonoyldehydro-3-(2-thienyl)alanine 4-methylpiperazide

Melting point: 172°-173° C.; yield: 90% of theory.

C₁₆ H₂₁ N₃ O₂ S; calculated: C 60.16%; H 6.63%; N 13.16%; S 10.04;found: C 60.18%; H 7.04%; N 13.16%; S 9.92%.

EXAMPLE 170 N-Crotonoyldehydro-3-(2-thienyl)alanine3-dimethylaminopropylamide

Melting point: 137°-138° C.; yield: 83% of theory.

C₁₆ H₂₃ N₃ O₂ S; calculated: C 59.78%; H 7.21%; N 13.07%; S 9.98%;found: C 59.44%; H 7.16%; N 13.02%; S 9.93%.

EXAMPLE 171 N-Crotonoyldehydro-3-(2-thienyl)alanine 6-aminohexylamide

Melting point: 113°-114° C.; yield: 70% of theory.

C₁₇ H₂₅ N₃ O₂ S; calculated: C 60.86%; H 7.51%; N 12.53%; S 9.56%;found: C 60.73%; H 7.58%; N 12.56%; S 9.37%.

EXAMPLE 172 N-Acetyldehydrophenylalanyl-3-(2-thienyl)dehydroalaninemethylamide

Melting point: 226° C.; yield: 89% of theory.

C₁₉ H₁₉ N₃ O₃ S; calculated: C 61.77%; H 5.18%; N 11.37%; S 8.68%;found: C 61.65%; H 5.25%; N 11.6%; S 8.63%.

EXAMPLE 173 N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanineanilide

Melting point: 240°-243° C.; yield: 56% of theory.

C₂₁ H₁₅ F₃ N₂ O₂ S; calculated: C 60.57%; H 3.63%; F 13.69%; N 6.73%; S7.70%; found: C 60.55; H 3.73%; F 13.5%; N 6.75%; S 7.71%.

EXAMPLE 174 N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine4-methylpiperazide

Melting point: 187°-188° C.; yield: 63.8% of theory.

C₂₀ H₂₀ F₃ N₃ O₂ S; calculated: C 56.73%; H 4.76%; N 9.92%; F 13.46%; S7.57%; found: C 56.57%; H 4.63%; N 9.98%; F 13.4%; S 7.56%.

EXAMPLE 175 N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanine3-dimethylaminopropylamide

Melting point: 152°-154° C.

C₂₀ H₂₂ F₃ N₃ O₂ S; TP 5

calculated: C 56.46%; H 5.21%; N 9.88%; F 13.4%; found: C 56.55%; H5.32%; N 10.0%; F 13.6%.

EXAMPLE 176 N-(3-Trifluoromethylbenzoyl)dehydro-3-(2-thienyl)alanineamide

Melting point: 205°-207° C.

C₁₅ H₁₁ F₃ N₂ O₂ S; calculated: C 52.94%; H 3.26%; N 8.23%; F 16.75%; S9.42%; found: C 53.05%; H 3.25%; N 8.26%; F 16.9%; S 9.46%.

EXAMPLE 177N-Acetyldehydro-3-(2-thienyl)alanyl-3-methyl-3-(2-thienyl)dehydroalaninehexylamide

Melting point: 110° C.; yield: 90% of theory.

C₂₃ H₂₉ N₃ O₃ S₂ ; calculated: C 60.10%; H 6.36%; N 9.14%; S 13.96%;found: C 60.20%; H 6.56%; N 9.26%; S 13.91%.

EXAMPLE 178 N-Nicotinoyl-3-(2-thienyl)dehydroalanine propargylamide

Melting point: 140°-143° C.; yield: 98% of theory.

C₁₆ H₁₃ N₃ O₂ S.H₂ O; calculated: C 58.34%; H 4.59%; N 12.76%; S 9.74%;found: C 58.21%; H 4.58%; N 13.15%; S 10.01%.

EXAMPLE 179 N-(2-Thienylacetyl)dehydro-3-(2-thienyl)alanine3-dimethylaminopropylamide

Melting point: 143° C.; yield: 74% of theory.

C₁₈ H₂₃ N₃ O₂ S₂ ; calculated: C 57.26%; H 6.14%; N 11.13%; S 16.99%;found: C 57.41%; H 6.09%; N 11.08%; S 17.05%.

EXAMPLE 180 N-Benzoyldehydro-3-(2-thienyl)alanine3-dimethylaminopropylamide

Melting point: 174°-176° C.; yield: 91% of theory. TP 5

C₁₉ H₂₃ N₃ O₂ S; calculated: C 63.84%; H 6.49%; N 11.76%; S 8.96%;found: C 63.92%; H 6.47%; N 11.91%; S 9.06%.

EXAMPLE 181 N-Benzoyldehydro-3-(2-thienyl)alanine anilide

Melting point: 231° C.; yield: 84% of theory.

C₂₀ H₁₆ N₂ O₂ S; calculated: C 68.94%; H 4.63%; N 8.04%; S 9.20%; found:C 69.20%; H 4.48%; N 8.03%; S 9.16%.

EXAMPLE 182 N-Benzoyldehydro-3-(2-thienyl)alanine methylamide

Melting point: 231° C. (decomposition); yield: 92% of theory

C₁₅ H₁₄ N₂ O₂ S; calculated: C 63.91%; H 4.93%; N 9.78%; S 11.20%;found: C 62.94%; H 5.10%; N 9.85%; S 11.30%.

EXAMPLE 813 N-Benzoyldehydro-3-(3-thienyl)alanine hexylamide

Melting point: 121° C.; yield: 95% of theory.

C₂₀ H₂₄ N₂ O₂ S; calculated: C 67.38%; H 6.79%; N 7.86%; S 8.99%; found:C 67.31%; H 6.85%; N 7.95%; S 8.89%.

EXAMPLE 184 N-Benzoyldehydro-3-(2-thienyl)alanine propargylamide

Melting point: 185°-186° C.; yield: 75% of theory.

C₁₇ H₁₄ N₂ O₂ S; calculated: C 65.79%; H 4.55%; N 9.03%; S 10.33%;found: C 65.93%; H 4.65%; N 8.88%; S 10.39%.

EXAMPLE 185 N-Benzoyldehydrophenylalanine hydrazide

Melting point: 151°-153° C.; yield: 28% of theory.

C₁₆ H₁₅ N₃ O₂ ; TP 5

calculated: C 68.31%; H 5.37%; N 14.94%; found: C 68.14%; H 5.53%; N14.89%.

EXAMPLE 186 N-Benzoyldehydrophenylalanine anilide

Melting point: 213°-233° C.; yield: 80% of theory.

C₂₂ H₁₈ N₂ O₂ ; calculated: C 77.17%; H 5.3%; N 8.18%; found: C 77.63%;H 5.7%; N 8.09%.

EXAMPLE 187 N-Benzoyldehydrophenylalanine methylamide

Melting point: 172°-174° C.; yield: 71% of theory.

C₁₇ H₁₆ N₂ O₂ ; calculated: C 70.6%; H 5.9%; N 9.7%; found: C 70.4%; H5.9%; N 9.8%.

EXAMPLE 188 N-Benzoyldehydrophenylalanine 1,1-dimethylpropargylamide

Melting point: 169°-174° C.; yield: 85% of theory.

C₂₁ H₂₀ N₂ O₂ ; calculated: C 75.88%; H 6.06%; N 8.43%; found: C 75.74%;H 6.07%; N 8.36%.

EXAMPLE 189 N-Benzoyldehydrophenylalanine hexylamide

Melting point: 139°-140° C.; yield: 63% of theory.

C₂₂ H₂₆ N₂ O₂ ; calculated: C75.4%; H 7.48%; N 7.99%; found: C 75.43%; H7.45%; N 8.09%.

EXAMPLE 190 N-Benzoyldehydrophenylalanine cyclohexylamide

Melting point: 197°-199° C.; yield: 85% of theory.

C₂₂ H₂₄ N₂ O₂ ; calculated: C 75.83%; H 6.94%; N 8.04%; found: C 75.81%;H 7.02%; N 8.08%.

EXAMPLE 191 N-Benzoyldehydrophenylalanine morpholide

Melting point: 158°-160° C.; yield: 63% of theory.

C₂₀ H₂₀ N₂ O₃ ; calculated: C 71.41%; H 5.99%; N 8.33%; found: C 71.3%;H 6.03%; N 8.2%.

EXAMPLE 192 N-Benzoyldehydrophenylalanine 4-methoxyphenyl hydrazide

Melting point: 207°-209° C.; yield: 38% of theory.

C₂₃ H₂₁ N₃ O₃ ; calculated: C 71.3%; H 5.46%; N 10.85%; found: C 71.4%;H 5.44%; N 10.96%.

EXAMPLE 193 N-Benzoyldehydrophenylalanine 2-phenylcyclopropylamide

Melting point: 140°-143° C.; yield: 89% of theory

C₂₅ H₂₂ N₂ O₂ ; calculated: C 78.51%; H 5.80%; N 7.33%; found: C 78.52%;H 5.83%; N 7.22%.

EXAMPLE 194 N-Benzoyldehydrophenylalanine 3,4,5-trimethoxy anilide

Melting point: 209°-212° C.; yield: 72% of theory.

C₂₅ H₂₄ N₂ O₅ ; calculated: C 69.43%; H 5.59%; N 6.48%; found: C 69.3%;H 5.55%; N 6.37%.

EXAMPLE 195 N-Benzoyldehydrophenylalanine 3-dimethylaminopropylamide

Melting point: 124°-126° C.; yield: 68% of theory.

C₂₁ H₂₅ N₃ O₂ ; calculated: C 71.77%; H 7.14%; N 11.96%; found: C71.67%; H 7.17%; N 12.13%.

EXAMPLE 196 N-Benzoyldehydrophenylalanine propargylamide

Melting point: 190°-191° C.; yield: 81% of theory.

C₁₉ H₁₆ N₂ O₂ ; calculated: C 74.98%; H 5.30%; N 9.21%; found: C 74.93%;H 5.37%; N 9.20%.

EXAMPLE 197 N-Acetyldehydro-3-(2-thienyl)alanine-2-(4-imidazolyl)ethylamide

Melting point: 105° C.; yield: 76.2% of theory.

C₁₄ H₁₆ N₄ O₂ S; calculated: C 55.24%; H 5.30%; N 18.41%; S 10.53%;found: C 55.26%; H 5.47%; N 18.41%; S 10.30%.

EXAMPLE 198 N-Acetyldehydro-3-(2-thienyl)alanine hexylamide

Melting point: 152°-153° C.; yield: 91.8% of theory.

C₁₅ H₂₂ N₂ O₂ S; calculated: C ;b 61.19%; H 7.53%; N 9.52%; S 10.89%;found: C 61.24%; H 7.57%; N 9.48%; S 10.98%.

EXAMPLE 199 N-Acetyldehydro-3-(2-thienyl)alanine2-phenylcyclopropylamide

Melting point: 204° C.; yield: 82.8% of theory.

C₁₈ H₁₈ N₂ O₂ S; calculated: C 66.23%; H 5.56%; N 8.58%; found: C66.30%; H 5.61%; N 8.67%.

EXAMPLE 200 N-Acetyldehydro-3-(2-thienyl)alanine benzylamide

Melting point: 193°-195° C.; yield: 93.3% of theory.

C₁₆ H₁₆ N₂ O₃ S; calculated: C 62.98%; H 5.37%; N 9.33%; S 10.67%;found: C 63.93%; H 5.31%; N 9.23%; S 10.40%.

EXAMPLE 201 N-Acetyldehydro-3-(2-thienyl)alanine3-dimethylaminopropylamide

Melting point: 137°-139° C.; yield: 78% of theory.

C₁₄ H₂₁ N₃ O₂ S; calculated: C 56.92%; H 7.17%; N 14.23%; S 10.85%;found: C 56.79%; H 7.09%; N 14.16%; S 10.71%.

EXAMPLE 202 N-Acetyldehydro-3-(2-thienyl)alanine piperidide

Melting point: 160°-161° C.; yield: 61.1% of theory.

C₁₄ H₁₈ N₂ O₂ S; calculated: C 60.40%; H 6.51%; N 10.06%; S 11.52%;found: C 60.6%; H 6.48%; N 10.1%; S 11.44%.

EXAMPLE 203 N-Acetyldehydro-3-(2-thienyl)alanine 4-methylpiperazide

Melting point: 183°-184° C.; yield: 68.3% of theory.

C₁₄ H₁₉ N₃ O₂ S; calculated: C 57.31%; N 6.53%; N 14.32%; S 10.93%;found: C 57.40%; H 6.46%; N 14.49%; S 10.96%.

EXAMPLE 204 N-Acetyldehydro-3-(2-thienyl)alanine 4-phenylpiperazide

Melting point: 197° C.; yield: 64.8% of theory.

C₁₉ H₂₁ N₃ O₂ S; calculated: C 64.20%; H 5.95%; N 11.82%; S 9.02%;found: C 64.09%; H 5.94%; N 11.84%; S 9.06%.

EXAMPLE 205 N-Crotonyldehydro-3-(2-thienyl)alanine 4-hydroxyanilide

Melting point: 245° C.; yield: 53% of theory.

C₁₇ H₁₀ N₂ O₃ S; calculated: C 62.18%; H 4.92%; N 8.53%; S 9.76%; found:C 61.97%; H 5.23%; N 8.57%; S 9.65%.

EXAMPLE 206 N-Acetyldehydro-3-(2-thienyl)alanine4-(2-hydroxyethyl)-piperazide

Melting point: 227°-230° C.; yield: 80.5% of theory.

C₁₅ H₂₁ N₃ O₃ S; calculated: C 55.71%; H 6.59%; N 12.99%; S 9.91%;found: C 55.68%; H 6.54%; N 12.97%; S 9.64%.

EXAMPLE 207 N-Acetyldehydro-3-(2-thienyl)alanine amide

Melting point: 189° C.; yield: 76.2% of theory.

C₉ H₁₀ N₂ O₂ S; calculated: C 51.41%; H 4.79%; N 13.32%; S 15.25%;found: C 51.34%; H 4.88%; N 13.33%; S 15.42%.

EXAMPLE 208 N-Acetyldehydro-3-(2-thienyl)alanine 2,2-dimethylhydrazide

Melting point: 174°-175° C.; yield: 59.3% of theory.

C₁₁ H₁₅ N₃ O₂ S; calculated: C 52.15%; H 5.97%; N 16.59%; S 12.66%;found: C 52.09%; H 6.00%; N 16.69%; S 12.50%.

EXAMPLE 209 N-Acetyldehydro-3-(2-thienyl)alanine anilide

Melting point: 95°-97° C.; yield: 73.4% of theory.

C₁₅ H₁₄ N₂ O₂ S; calculated: C 62.92%; H 4.93%; N 9.78%; S 11.20%;found: C 62.85%; H 4.99%; N 9.83%; S 11.32%.

EXAMPLE 210 N-Acetyldehydro-3-(2-thienyl)alanine b4-methylcyclohexylamide

Melting point: 195°-197° C.; yield: 57.4% of theory.

C₁₆ H₂₂ N₂ O₂ S; calculated: C 62.71%; H 7.24%; N 9.14%; S 10.47%;found: C 62.73%; H 7.37%; N 8.99%; S 10.53%.

EXAMPLE 211 N-Acetyldehydro-3-(2-thienyl)alanine 3-morpholinopropylamide

Melting point: 135°-137° C.; yield: 48.9% of theory.

C₁₆ H₂₃ N₃ O₃ S; calculated: C 56.95%; H 6.87%; N 12.45%; S 9.51%;found: C 56.92%; H 6.87%; N 12.30%; S 9.59%.

EXAMPLE 212 N-Acetyldehydro-3-(2-thienyl)alanine 1-phenylethylamide

Melting point: 171°-173° C.; yield: 50.9% of theory.

C₁₇ H₁₈ N₂ O₂ S; calculated: C 64.94%; H 5.77%; N 8.91%; S 10.20%;found: C 65.14%; H 5.91%; N 8.89%; S 10.30%.

EXAMPLE 213 N-Acetyldehydro-3-(2-thienyl)alanine 3-carboxypropylamide

Melting point: 195°-197° C.; yield: 65.9% of theory.

C₁₃ H₁₆ N₂ O₄ S; calculated: C 52.69%; H 5.44%; N 9.45%; S 10.82%;found: C 52.87%; H 5.55%; N 9.54%; S 10.98%.

EXAMPLE 214 N-Acetyldehydro-3-(2-thienyl)alanine hydrazide

Melting point: 170° C.; yield: 75.5% of theory.

C₉ H₁₁ N₃ O₂ S.H₂ O calculated: C 44.43%; H 5.39%; N 17.27%; S 13.18%;found: C 44.21%; H 5.37%; N 17.30%; S 13.26%.

EXAMPLE 215 N-Acetyldehydro-3-(2-thienyl)alanine 2-sulphonic acidethylamide

Melting point: 192°-194° C.; yield: 68.7% of theory.

C₁₁ H₁₄ N₂ O₅ S₂ ; calculated: C 41.50%; H 4.42%; N 8.80%; S 20.14%;found: C 41.36%; H 4.60%; N 8.73%; S 19.99%.

EXAMPLE 216 N-Acetyldehydro-3-(2-thienyl)alanine1-ethinylcyclohexylamide

Melting point: 223°-224° C.; yield: 82.5% of theory.

C₁₇ H₂₀ N₂ O₂ S; calculated: C 64.54%; H 6.37;l %; N 8.86%; S 10.12%;found: C 64.37%; H 6.26%; N 8.70%; S 10.24%.

EXAMPLE 217 N-Acetyldehydro-3-(2-thienyl)alanine benzyloxyamide

Melting point: 142°-144° C.; yield: 47.5% of theory.

C₁₆ H₁₆ N₂ O₃ S; calculated: C 60.74%; H 5.10%; N 8.86%; S 10.13%;found: C 60.60%; H 5.15%; N 8.99%; S 10.04%.

EXAMPLE 218 N-Acetyldehydro-3-(2-thienyl)alanine 2-hydroxyethylamidephosphate

Melting point: 180°-182° C.; yield: 35.9% of theory

C₁₁ H₁₅ N₂ O₆ PS.H₂ O; calculated: C 37.50%; H 4.86%; N 7.95%; P 8.79%;S 9.11%; found: C 36.96%; H 4.78%; N 7.99%; P 8.69%; S 8.91%.

EXAMPLE 219 N-Acetyldehydro-3-(2-thienyl)alanine morpholide

Melting point: 159° C.; yield: 82.7% of theory.

C₁₃ H₁₆ N₂ O₃ S; calculated: C 55.69%; H 5.75%; N 9.99%; S 11.22%;found: C 55.80%; H 5.73%; N 10.09%; S 11.22%.

EXAMPLE 220 N-Acetyldehydro-3-(2-thienyl)alanine propargylamide

Melting point: 202°-204° C.; yield: 72% of theory.

C₁₂ H₁₂ N₂ O₂ S; calculated: C 58.05%; H 4.87%; N 11.28%; S 12.91%;found: C 57.96%; H 4.9%; N 11.33%; S 12.96%.

EXAMPLE 221 N-Acetyldehydro-3-(2-thienyl)alanine 3,4,5-trimethoxyanilide

Melting point: 203°-205° C.; yield: 51.3% of theory

C₁₈ H₂₀ N₂ O₅ S; calculated: C 57.43%; H 5.36%; N 7.44%; S 8.52%; found:C 57.50%; H 5.32%; N 7.39%; S 8.63%.

EXAMPLE 222 N-acetyldehydro-3-(2-thienyl)alanine2-(benzothiazol-2-yl)-hydrazide

Melting point: 183°-185° C.; yield: 22% of theory.

C₁₆ H₁₄ N₄ O₂ S₂ ; calculated: C 53.61%; H 3.94%; N 15.63%; S 17.89%;found: C 53.41%; H 4.06%; N 15.45%; S 17.89%.

What is claimed is:
 1. A pharmaceutical composition containing as anactive ingredient an effective amount of 1 to 100 mg of a compound whichis a dehydrooligopeptide of the following general formula or its salt##STR4## in which R₁ is hydrogen; alkanoyl having from 2 to 6 carbonatoms; benzoyl or naphthoyl each unsubstituted or substituted by from 1to 3 halogen atoms or by trifluoromethyl; heteroaryl having from 5 to 7ring members and containing from 1 to 3 hetero-atoms which are the sameor different and each of which is nitrogen, sulfur or oxygen and onwhich there is a carbonyl group;each of R₂, R₇ and R₁₂ is a hydrogen;each of R₃, R₈ and R₁₃ is hydrogen; straight chain or branched alkylhaving from 1 to 6 carbon atoms; phenylalkyl having from 1 to 4 carbonatoms, unsubstituted or substituted by one or more halogen atoms, nitro,hydroxyl, methoxy or alkyl having from 1 to 4 carbon atoms; each of R₄and R₉ is hydrogen; each of R₅, R₁₀ and R₁₄ is hydrogen or alkyl havingfrom 1 to 6 carbon atoms; R₇ and R₈, taken together, form a divalentalkylene chain having three or four carbon atoms; each of R₆ and R₁₁ isphenyl or naphthyl, unsubstituted or substituted by halogen atoms; aheterocyclic radical having from 5 to 7 ring members and 1 to 2hetero-atoms each of which is nitrogen, sulphur or oxygen, and isunsubstituted or substituted by halogen atoms or by nitro; or alkylhaving from 1 to 6 carbon atoms; R₆ taken together with R₅ and thecarbon atoms, at the double bond, linking them, form, a cycloalkylideneor cycloalkylidene ring, having from 3 to 7 carbon atoms; and R₁₅ ishydroxyl, hydrazinyl which is unsubstituted or substituted by loweralkyl, straight-chain or branched, mono or di-(alkyl- or alkenyl-) aminohaving from 1 to 6 carbon atoms in each alkyl or alkenyl moiety and isunsubstituted or substituted by amino, lower mono- or dialkylamino; m,n, p and q are the same or different and each represents a figure 0 or1, with the proviso that m, n, p and q may not all be 1 at the same timeand an inert pharmaceutical carrier.
 2. A pharmaceutical compositionaccording to claim 1, whereinR₁ is ##STR5## R₂, R₃, R₄ are eachhydrogen; R₅ is hydrogen or methyl; R₆ is ##STR6## R₆ taken togetherwith R₅ and the carbon atoms, at the double bond linking them, iscyclohexylidene or cyclohexenylidene; R₇ is hydrogen; R₈ is ##STR7## R₇and R₈, taken together, form the --CH₂ --CH₂ --CH₂ -- radical; R₉ ishydrogen R₁₀ is hydrogen; R₁₁ is ##STR8## R₁₂ is hydrogen; R₁₃ is##STR9## R₁₄ is hydrogen; R₁₅ is ##STR10## m=0; and n, p and q are each0 or
 1. 3. A pharmaceutical composition according to claim 1 or 2wherein the effective amount of active ingredient is 2 to 40 mg.
 4. Apharmaceutical composition of claim 1 consisting essentially of, as anactive ingredient an amount of a compound as defined in claim 1effective for histologic action, and a sterile or isotonic aqueouscarrier therefor.
 5. A composition according to claim 1 or 2 containingfrom 1 to 90% of the said active ingredient by weight.
 6. A medicamentin unit dosage form comprising a composition of claim
 1. 7. A medicamentof claim 6 in the form of ampoules.
 8. A composition according to claim2 in which the dehydrooligopeptide is N-Acetyldehydrophenylalanine.
 9. Acomposition according to claim 2 in which the dehydrooligopeptide isN-Acetyldehydrophenylalanyl-L-(p-nitrophenyl) alanine.
 10. A compositionaccording to claim 2 in which the dehydrooligopeptide isN-Acetyldehydro-3-(2-furyl)alanyl-L-tyrosine.
 11. A compositionaccording to claim 2 in which the dehydrooligopeptide isN-Acetyldehydro-3-cinnamenylalanyl-L-tyrosine.
 12. A compositionaccording to claim 2 in which the dehydrooligopeptide isN-Acetyldehydro-3-(2-thienyl)analyl-L-tyrosine.
 13. A compositionaccording to claim 2 in which the dehydrooligopeptide isN-Acetyldehydrophenylalanyldehydrotyrosine.
 14. A composition accordingto claim 2 in which the dehydrooligopeptide isN-Acetyldehydrophenylalanyldehydro(4-chlorophenyl) alanine.